Novartis’ HRO761 is an oral allosteric WRN helicase inhibitor, aimed at treating MSI-high and dMMR tumors. This article details the discovery of HRO761 and highlights the importance of selecting appropriate assays during early HTS as well as transferable medicinal chemistry strategies to optimize permeability and solubility through the modulation of LipE, neutral TPSA, chameleonicity, and non-classical zwitterions. It also explores the X-ray structure of HRO761 bound to WRN, how it differentiates from Vividion's VVD-214, its preclinical activity, clinical status, chemical synthesis, and more!

ORIC-944 is a second-generation, orally bioavailable PRC2 inhibitor, targeting the allosteric EED subunit. EZH2 inhibitors typically require frequent dosing due to poor drug-like properties. This article describes the previously undisclosed structure-based design of ORIC-944 into a potential best-in-class PRC2 inhibitor with enhanced solubility, metabolic stability, and prolonged clinical half-life compared to EZH2 inhibitors. It also highlights ORIC-944's capability to reprogram refractory, AR-independent prostate tumors to an AR-dependent state, the synthesis, clinical data, and more!

Pfizer’s oral, CDK4-selective inhibitor PF-07220060 has the potential to revolutionize treatment of HR+/HER2- breast cancer through avoiding the neutropenia DLTs associated with SoC CDK4/6 drugs and permitting greater coverage of the desired CDK4 target. Our full article outlines data presented at AACR 2024, covering the molecule’s course from in silico-informed screen, through structurally enabled optimization against CDK6 and GSK-3β to promising preclinical profile. Fresh clinical data showed efficacy and tolerability supporting PF-07220060's clinical progression.

TNG348 is a synthetic lethal inhibitor of USP1 by Tango Therapeutics. Inhibiting USP1 disrupts DNA repair and replication mechanisms leading to the selective death of BRCA1/2-mutant cancer cells. Despite the clinical benefit of PARPi in treating BRCA-mutated or HRD+ tumors, some patients exhibit an inadequate response or develop resistance. USP1 inhibitors may hold promise in meeting this unmet clinical demand. This case study highlights USP1 as a synthetic lethal target, the current competitive landscape, how the Tango team overcame high microsomal clearance and hERG liabilities, and more.

AstraZeneca has joined the race to gain approval for a first-in-class, orally bioavailable selective inhibitor of CDK2 with AZD8421, which was recently disclosed at the AACR San Diego 2024 “New Drugs on the Horizon” series. CDK2-selective inhibitors are a hot area right now, with their promise to overcome the resistance against approved CDK4/6 inhibitors. Read the full case study to learn about the CDK2-selective competitive landscape, the structural and kinetic data which underpin AZD8421’s CDK-selectivity and the preclinical activity data which has propelled it into the clinic.

BLU-222 is a potential first-in-class, orally bioavailable selective inhibitor of CDK2 discovered and currently in development by Blueprint Medicines for the treatment of advanced solid tumors. Read the full case study to learn about the competitive landscape of CDK inhibitors, the discovery story enabled by the DiscoveRx KINOMEscan screening platform, how exquisite kinome selectivity can be achieved despite ~100% active site sequence similarity between CDK1/2, how this molecule can potentially treat CCNE1-amplified and CDK4/6i-resistant tumor models, interim clinical data, and more.

PRMT5 is an epigenetic “synthetic lethality” target that has attracted much attention among drug hunters. The first generation of PRMT5 inhibitors was limited by systemic toxicities resulting in a cooling of industry interest, until the recent identification of tumor-specific inhibitors. These second-generation compounds target the MTA:PRMT5 complex in MTAP-deleted cancers—15% of all tumors—leading to a revival of the target. Read on to find out which companies are prevailing in the search for a first-in-class PRMT5 inhibitor and how their clinical compounds differentiate.

SGR-1505, the first in-house clinical compound developed at Schrödinger, is an oral, allosteric MALT1 inhibitor currently in the clinic for the treatment of mature B cell malignancies. The discovery effort, disclosed at the ACS Spring 2024 meeting, was completed in an impressive 10 months, starting from a published scaffold. SGR-1505 demonstrated preclinical single-agent and combination activity as well as inducing resensitization in BTK and BCL-2 inhibitor-resistant tumors. The compound is currently progressing in a Ph. I trial in patients with mature B cell malignancies.

Deciphera’s DCC-3116 is an oral ULK1/2 inhibitor targeting the autophagy pathway, a key mechanism of tumor survival and resistance to targeted therapy. Currently in two open-label Ph. I/II trials as a monotherapy and in combination with RTK pathway inhibitors, the structure and discovery of this first-in-class compound were recently presented at the ACS Spring 2024 meeting.

TNG462, developed by Tango Therapeutics, is a potential best-in-class, oral, protein arginine methyltransferase 5 (PRMT5) inhibitor currently in Ph. I/II clinical trial for MTAP-deleted solid tumors. TNG462 is designed to cooperatively bind to PRMT5 when complexed with its endogenous inhibitor methylthioadenosine (MTA), which accumulates in MTAP-deleted tumors. This triggers synthetic lethality in cells with an MTAP-deletion and spares healthy tissues with low MTA levels. A CNS-permeable analogue, TNG908, is also entering clinical trials for MTAP-deleted glioblastoma.

VVD-214/RO7589831 is an oral covalent, reversible, and allosteric inhibitor of WRN helicase discovered by the San Diego-based biotech Vividion Therapeutics and being developed by Roche for tumors marked by microsatellite instability and/or mismatch repair deficiency. Vividion has utilized its chemoproteomics platform to discover and develop novel treatment options for oncology targets. The structure and initial preclinical pharmacology data for VVD-214 were recently disclosed at the AACR Annual Meeting 2024 in San Diego. VVD-214 is currently being evaluated in a Ph. I trial.

ORIC-533, a potential best-in-class oral inhibitor of CD73 from ORIC Pharmaceuticals, is currently in a Ph. Ib trial for relapsed/refractory multiple myeloma (MM). It inhibits the CD73-mediated conversion of AMP to adenosine which generates an immunosuppressive tumor microenvironment and has the potential to be a next-generation immunotherapy. The in-depth use of X-ray structures led the team to discover a novel set of phosphonate bioisosteres which acheived bioavailability in a polar scaffold. The structure and discovery of ORIC-533 were recently disclosed at the ACS Spring 2024 Meeting.

MK-1084 is an oral covalent inhibitor of KRAS(G12C) being developed by Merck (as part of a collaboration with Taiho and Astex), which is currently in a Ph. I trial (NCT05067283) for the treatment of solid tumors either as a monotherapy or in combination with their checkpoint inhibitor immunotherapy pembrolizumab (Keytruda™). The medicinal chemistry story was recently presented at the ACS Spring 2024 meeting in New Orleans, following a presentation of the Ph. I interim results by Merck at ESMO in Oct. 2023.

GDC-1971 is an orally bioavailable allosteric inhibitor of the SHP2 phosphatase discovered by Relay Therapeutics, and in clinical development by Genentech both as a monotherapy and in combination with several anticancer therapies. SHP2 inhibitors are being hotly pursued since they may combine with numerous classes of clinically important agents. This article provides a primer on SHP2 as an oncology target, the disclosed molecules in the space, how RLY-1971 was identified, and what the industry is watching for.

Olutasidenib, discovered by Forma Therapeutics and marketed by Rigel, is an oral, brain-penetrant, selective mIDH1 inhibitor. It was granted Orphan Drug Designation and approved in December 2022 by the FDA for adults with relapsed/refractory acute myeloid leukemia. Approval was granted based on a Ph. I/II trial showing a 35% CR+CRh rate and a favorable 25.9-month median duration. This article describes the discovery and development of olutasidenib, how it is distinct from other mIDH inhibitors, and its potential in treating gliomas.

STC15 is Storm Therapeutics' first-in-class and first-to-clinic inhibitor of the post-transcriptional RNA modifier, METTL3, which progressed from HTS hit to clinical development in less than three years. METTL3 inhibitors have been previously identified, but no METTL3 inhibitors have entered clinical development until now. In this article, we explore METL3 as a therapeutic target, highlight the discovery story of STC15, its fascinating mechanism of action, provide the latest clinical development update, and much more.

Momelotinib is a JAK inhibitor approved by the FDA in September 2023 for treating myelofibrosis. Last year, the molecule’s co-inventors, Andrew Wilks and Christopher Burns, gave a Drug Hunter Flash talk about the development of this drug with a fascinating mechanism of action.

In celebration of the molecule’s advancement, here we recap their brilliant story, including Wilks’ discovery of the JAK kinases and how he gave them their name, and the long, sometimes fraught journey of momelotinib through several companies before its acquisition and commercialization by GSK.

While KRAS(G12C) has been the most readily targeted form of KRAS thanks to its reactive cysteine residue, other mutations such as KRAS(G12D) make up the majority of KRAS-mutated cancers. In this roundup, we highlight 12 inhibitors, degraders, and other molecules that reflect progress in overcoming this challenge, including some of the first clinical candidates targeting non-KRAS(G12C)-mutant tumors, and why these molecules are notable.

RLY-2608 is an oral, mutant-selective PI3Kα allosteric inhibitor by Relay Therapeutics. Current FDA-approved PI3Kα modulator (alpelisib) and a clinically advanced molecule (inavolisib) are limited by their off-target toxicities associated with the inhibition of WT PI3Kα, leading to hyperglycemia and rash. RLY-2608 is currently in a Ph. I as a single agent and in combination with fulvestrant for HR+/HER2- breast cancer treatment. This article reviews the discovery of RLY-2608, its mechanism of mutant selectivity, how it compares to other molecules, recent clinical developments, and more.

The Hippo pathway is a well-known regulator of tissue growth and organ size and gets its name from the Hippo kinase (Hpo in Drosophila, MST1/2 in humans), which when mutated leads to “hippopotamus”-like tissue overgrowth. Recently, industry interest in the pathway has increased thanks to several independent studies in 2023, and the field appears to be at an important inflection point for drug discovery. Here we review current efforts and therapeutic hypotheses for drugging the TEAD transcription factors in cancer, including clinical molecules, paralog-selective molecules, and TEAD degraders.

KIN-3248 (Kinnate Biopharma) is a next-generation, irreversible, pan-fibroblast growth factor receptor inhibitor (FGFRi) in a first-in-human (FIH) dose-escalation study (NCT05242822) in adults with advanced tumors harboring FGFR2 and FGFR3 gene alterations. The program is an excellent case study for rational covalent drug design to address kinase mutations while maintaining sufficient PK properties for oral daily dosing in humans.

Nuvalent’s lead compound, NVL-520, is an oral, brain-penetrant, TRK-sparing, and potential best-in-class ROS1 kinase inhibitor that recently entered Ph. II of the ARROS-1 trial (NCT05118789) in patients with advanced ROS1-positive NSCLC. This article highlights what makes the Nuvalent’s NVL-520 program scientifically notable, including what gives it a potential best-in-class profile as a ROS1 inhibitor, the emerging toxicology of hard-to-avoid off-targets, an interesting synthetic route to the small macrocycle, and more.

STX-721 is an oral, covalent, mutant-selective inhibitor of EGFR and HER2 Exon 20 insertion (ex20ins) mutants, a well-validated target that saw its first approval with mobocertinib in 2022. Inhibition of wild-type (WT) EGFR is well-established to cause skin and gut toxicities, and selective inhibition of EGFR ex20ins mutants over WT may also allow greater efficacy to be seen at tolerated doses. This is an excellent case study for PK optimization with a covalent inhibitor, and [...]

There continue to be opportunities for another KRAS(G12C) inhibitor to prove itself best-in-class.

This roundup highlights twelve KRAS(G12C) molecules to know, with links to recent case studies on Drug Hunter going in more detail.

Recently, brain-penetration data via PET was reported for several KRAS(G12C) inhibitors including AZD4747, adagrasib, and sotorasib. AZD4747 has been updated with additional PET data for KRAS(G12C) inhibitors from a recent conference in the UK. Additionally, Tobias Biberger has contributed an update to the recent AZD4747 case study highlighting its interesting medicinal chemistry route with some surprising steps including manipulations of an unprotected phenol, and the synthesis of its PET tracer...

Amgen’s first-in-class KRAS(G12C) inhibitor, sotorasib, recently encountered an unexpected but significant regulatory setback with the FDA at its October 5th Oncologic Drugs Advisory Committee Meeting (ODAC). Full approval for sotorasib had widely been expected in the industry, but the FDA ODAC voted 10 to 2 that progression-free survival (PFS), the key endpoint for comparing sotorasib to docetaxel chemotherapy, could not be reliably interpreted in the pivotal CodeBreaK200 (NCT04303780) study for KRASG12C+ late-stage NSCLC. What happened, and what does it mean for KRAS inhibitors?

STX-478 is a wild-type-sparing, oral, CNS-penetrant, novel allosteric inhibitor of mutant phosphatidylinositol-3 kinase α (PI3Kα), targeting a cryptic pocket near the ATP-binding site. PI3Kα plays a central role in many cancers, and has been recently highlighted in coverage of 2021 Molecule of the Year nominee and PI3Kα degrader inavolisib. Currently approved PI3Kα modulators are limited by their off-target activities on WT PI3Kα and other kinases, leading to significant side effects including hyperglycemia and rash.

Nurix recently unveiled their second clinical BTK degrader, NX-5948, which is in Ph. Ia/Ib for patients with advanced B-cell malignancies (NCT05131022). A novel CRBN ligand was developed to remove IKZF1/3 degradation activity, distinguishing NX-5948 from their earlier disclosed dual BTK-IKZF1/3 degrader NX-2127, which is currently in Ph. I for relapsed/refractory B-cell malignancies (NCT04830137). The potent BTK degrader NX-5948 has displayed CNS penetration preclinically, allowing for primary CNS lymphoma (PCNSL) participants to be included in the clinical study.

PF-9363 (CTx-648) is a first-in-class, oral inhibitor of the KAT6A/B histone lysine acetyltransferases (HATs) for the treatment of ER+/luminal & KAT6A+ breast cancer discovered by Melbourne’s Cancer Therapeutics CRC (CTxT) and Pfizer, San Diego. This article discusses why the molecule is scientifically notable in drug discovery for epigenetic targets and transferable scientific insights from its decade-long KAT6 campaign including its target rationale, hit-finding and lead optimization, synthesis and relevant clinical data.

Genentech’s divarasib is a KRASG12C inhibitor in Ph. III for non-small cell lung cancer, making it the most advanced KRASG12C inhibitor after the accelerated approvals of Amgen’s sotorasib and Mirati’s adagrasib. Efficacy with the molecule positions it well at a pivotal moment following sotorasib's recent FDA setback and BMS’s acquisition of adagrasib. Why divarasib is a big deal and what's notable about it in this full article.

LUNA18 is an orally bioavailable, cell-penetrant, macrocyclic peptide pan-RAS inhibitor (Chugai ’21Q3 earnings call) intended for the treatment of KRAS-mutant cancers. It disrupts the protein-protein interaction between KRAS and SOS, preventing RAS activation.

TEAD1-4, nuclear transcription factors that are key effectors of the Hippo pathway, have become of increased recent interest in part due to the potential for TEAD inhibitors to synergize with RAS inhibition. GNE-7883, a pan-TEAD allosteric inhibitor tool from Genentech demonstrated in vivo proof-of-concept for combination therapy with a KRAS(G12C) inhibitor. This article highlights the rational design of an allosteric pan-TEAD inhibitor from a FRET-based HTS, the activities of GNE-7883 in YAP/TAZ-dependent cancers, and the potential applications of TEAD inhibitors in precision oncology.

RAPT Therapeutics, formerly known as FLX Bio, was spun out of Flexus Biosciences after its billion-dollar acquisition by BMS for Flexus’s immuno-oncology IDO1 program. While the IDO1 molecule unfortunately did not show efficacy in Ph. III trials in combination with BMS’s PD-1 inhibitor nivolumab, RAPT Therapeutics appears to be having better luck with its potentially first-in-class CCR4 inhibitors FLX475 (for immune-oncology) and RPT193 (for atopic dermatitis). Oral FLX475 (100 mg QD, human T1/2 = 72 h) appears to shrink EBV+ tumors both as a monotherapy and in combination

Vorasidenib (AG-881) is a brain-penetrant allosteric inhibitor of mutant isocitrate dehydrogenases 1 and 2 (mIDH1/2) from Agios and Celgene that made headlines summer 2023 due to its stunning efficacy for treatment of glioma in patients with mIDH1/2.

This Featured Case Study reviews how it was discovered, how it works, and why it matters.

The FGFR family of receptors are well-validated targets in cancer. While specific FGFRs like FGFR2 can drive cancers like cholangiocarcinoma, broad inhibition of FGFRs leads to significant off-target toxicities. Relay Therapeutics captured industry attention when they announced the discovery of an FGFR2 isoform-selective inhibitor, lirafugratinib, using a molecular dynamics simulations approach. This article provides an overview of the pan-FGFR landscape, explores the specifics of the FGFR2 selectivity, preclinical pharmacology, and early clinical data for this remarkable molecule.

AZD4747 is a CNS-penetrant, oral KRAS G12C covalent inhibitor for the treatment of CNS-metastatic KRAS-mutant cancers. KRAS inhibitors have tended to be quite large and fall outside the range of physicochemical properties generally required for CNS permeability. (MW < 360 Da, cLogD < 2, TPSA < 90 Å2. AZD4747 is much smaller than marketed KRAS G12C inhibitors but maintains exceptional cellular potency. The team also encountered an unexpected toxicity that scientists working on covalents should pay attention to.

A diaziridine-based tumor-activated prodrug for AKR1C3-expressing cancers from a defunct Bay Area biotech. OBI-3424 (formerly TH-3424) is a tumor-activated prodrug in Ph. II that releases DNA-crosslinking diaziridine phosphamide (remniscent of thioTEPA) upon activation by the NAD(P)H-dependent aldoketoreductase, AKR1C3, which is differentially expressed in many cancers. The molecule was originated at...

The RAS proteins, KRAS4A, KRAS4B, HRAS, and NRAS control diverse cellular processes, and gain-of-function mutations in RAS genes are found in ~25% of cancers in humans, with KRAS mutations accounting for up to 85% of RAS mutations across cancers. While KRAS^G12C has been successfully targeted by approved drugs sotorasib and adagrasib and numerous candidates [...]

This article highlights million-dollar molecules that were recently in the news with related patent applications that give clues to their structures and properties. This edition includes Maze’s glycogen synthase 1 (GYS1) inhibitors that were recently licensed to Sanofi, allosteric androgen receptor (AR) modulators that may be of interest to targeted protein degradation researchers, brain-penetrant HER2 and ROCK2 inhibitors, and MDM2 degraders.

CFT1946 from C4 Therapeutics is a potent, selective, and orally bioavailable bifunctional degrader of mutant BRAF in Ph. I/II for the treatment of BRAF-driven solid tumors, alone and in combo with a MEK1/2 inhibitor (trametinib) (NCT05668585). BRAF-V600X is clinically validated with approved drugs (e.g. vemurafenib), but traditional inhibitors face challenges in selectivity over wildtype BRAF and can cause paradoxical RAF activation. [...]

The accelerated approvals of Ras(OFF)-targeting KRAS G12C inhibitors sotorasib and adagrasib, decades in the making, marked the beginning of a new phase of KRAS drug discovery. While an increasing number of follow-on KRAS inhibitors are emerging with similar mechanisms of action, Revolution Medicines’ 2023 Molecule of the Year Nominee, RMC-6291, is representative of a completely novel approach that could become a strong addition to the clinical toolbox for KRAS, but also serves as proof-of-concept for a new class of small molecule therapeutics entirely.

A second-generation AR bifunctional degrader for drug-resistant prostate cancer. ARV-766 is Arvinas’ second bifunctional CRL4 CRBN E3 ligase-based androgen receptor (AR) degrader to enter the clinic for the treatment of prostate cancer (PCa), after ARV-110 (bavdegalutamide) . The glutarimide recruiting element is notable as it is simpler than [...]

The first non-ATP-competitive inhibitor of the long-pursued PI3Kδ kinase. Phosphatidylinositol-3-kinase (PI3K) has received intense attention as a drug target from the pharmaceutical industry due to its central role in cancer and involvement in other indications. As described in our recent overview of this area, numerous compounds have [...]

Indoleamine 2,3-dioxygenase 1 (IDO1) is an extrahepatic tryptophan-metabolizing enzyme which is believed to contribute to the evasion of the immune system by tumors , making it an attractive target for cancer immunotherapy, especially in combination with immune [...]

FGF401 (roblitinib) is a highly selective, reversible-covalent inhibitor of the kinase FGFR4, a receptor that can drive progression of certain cancers. The Novartis team found that the FGFR4 protein has a high re-synthesis rate and therefore would require significant drug exposure to have a meaningful effect, so they deprioritized [...]

A-1331852 is a highly potent, orally bioavailable inhibitor of BCL-XL, blocking a protein-protein interaction resulting in tumor cell apoptosis. The compound was an important tool compound for understanding the biology of BCL-family protein inhibitors (particularly around heme toxicities), and ultimately led to the development of an [...]

April 2020’s molecule, the Mirati KRAS G12C inhibitor MRTX849 , has been a hotly followed compound in development as it is the closest clinical KRAS inhibitor to the likely soon-to-be approved AMG-510 (sotorasib). The KRAS clinical race easily would have been the most followed development story of 2020 had it not been for COVID, due to the [...]

Gamma-secretase is most well-known as a target for Alzheimer’s disease, though such programs have not been successful to date. Nirogacestat is a gamma-secretase inhibitor that Pfizer originally intended to treat AD, but found life at Springworks Therapeutics as a treatment as a first-in-class drug for rare and aggressive desmoid tumors (DTs). Nirogacestat received the first FDA approval for a treatment for desmoid tumors in Nov. 2023, and this article reviews how it was discovered, how the therapeutic hypothesis emerged after confusing assay disconnects, and lessons learned from the program.

Tumors can evade the immune system through the recruitment of regulatory T cells (Treg) which limit the activation and expansion of effector T cells (Teff). IKZF2 (Helios) is an Ikaros transcription factor family member that is expressed in a majority of Treg cells [...]

Acute myeloid leukemia (AML) remains difficult to treat, with few novel therapies approved in the last three decades. A subset of these aggressive leukemias, mixed lineage leukemias , are driven by fusions between the MLL1 gene (“Mixed Lineage Leukemia”, or KMT2A) and more than 80 [...]

The AACR 2023 first disclosures presented in the Chemistry in Cancer Research’s “New Drugs on the Horizon” sessions are always fascinating. This article contains the structures of all of the novel small molecule first disclosures presented at AACR in the session, along with notes on their significance, and another molecule disclosed in the [...]

Overview. Cyclin-dependent kinase ( CDK2 ) is a target of recent interest , but selectivity has been challenging to obtain. This molecule provides an interesting example of AI being applied to lead generation. Macrocycles can be challenging to design rationally, but can lead to a variety of favorable properties (e.g. in addressing resistance [...]

M4205 (IDRX-42) is a highly selective type II receptor tyrosine kinase inhibitor of KIT, discovered by Merck KGaA and currently being developed by IDRx. The molecule is a notable example of kinase selectivity achieved with a non-classical hinge binder. M4205 (IDRX-42) has received an Orphan Drug designation and is currently being evaluated in a Ph. I/Ib FIH trial for GIST, one of the most common mesenchymal neoplasms in the GI tract.

Ziftomenib (KO-539) is an oral menin-MLL1 protein-protein interaction inhibitor being developed for acute myeloid leukemia (AML) by Kura Oncology. This Sep. ’22 Molecule of the Month inhibits the protein–protein interaction between menin and mixed lineage leukemia (MLL) fusion proteins, an interaction that drives many leukemias. Early data [...]

MRTX1133 is a non-covalent, reversible, long-acting inhibitor of KRAS G12D entering clinical development for cancer as an oral agent . Mutant KRAS proteins are well-known drivers of cancer, and only in recent years have the first KRAS inhibitors been approved. These inhibitors are covalent and only work on the KRAS G12C mutation, as they bind [...]

In this update of small molecules in the news for February 2023, we will cover recent: - Molecules in Motion : clinical trial updates and FDA filings - Negative Readouts : halted, discontinued or altered clinical trials - Million-Dollar Molecules : recent M&A’s, IPOs, and other fundraising - Potential Approvals : recent NDA filings and [...]

The first approved non-covalent BTK inhibitor. As the nexus of the B cell receptor (BCR) signaling pathway , BTK has been a hotly pursued target in B-cell-mediated cancers and immunological diseases , as evidenced by the many BTK inhibitors we’ve highlighted in just the past few years. Recently, pirtobrutinib (Jaypirca, LOXO-305) received [...]

What is it? Elacestrant ( Orserdu ) is an oral, selective estrogen receptor modulator and degrader (SERM/SERD) that was recently approved for ER-positive, HER2-negative, estrogen receptor ɑ (ESR1)-mutated advanced or metastatic breast cancer (345 mg PO QD) based on progression-free survival (PFS) data from EMERALD ( NCT03778931 ). As the [...]

A protein-protein interaction inhibitor for a challenging-to-drug master transcription factor. OICR12694 is an oral protein-protein interaction inhibitor targeting the challenging-to-drug oncogenic transcription factor, B cell lymphoma 6 (BCL-6) . As a master regulator of B cell differentiation in germinal centers and hence a common driver of [...]

What is it? Saridegib (IPI-926, patidegib) is a Smoothened receptor (SMO) antagonist and hedgehog pathway inhibitor currently in Ph. III trials for Gorlin syndrome. The molecule is a semisynthetic analog of the naturally-occuring SMO antagonist , cyclopamine, and has a long history and originates from Infinity Pharmaceuticals . After a [...]

Mirati’s “Breakthrough” KRAS G12C inhibitor, adagrasib, was granted accelerated approval by the FDA in 2022. As it follows Amgen’s first-in-class KRAS G12C inhibitor, sotorasib, adagrasib is constantly scrutinized for any evidence it may be different, or better, than sotorasib. This deep dive reviews the current understanding on how adagrasib [...]

What is it? RMC-5552 is a potential first-in-class, bi-steric, mTOR1-selective inhibitor in Ph. I/IIb ( NCT04774952, NCT05557292) as an IV agent to treat tumors with hyperactive mTORC1 signaling. This previously highlighted molecule is a bi-steric inhibitor containing an allosteric C32-hydroxy rapamycin derivative linked to an orthosteric [...]

Inavolisib is a PI3Kα isoform-selective kinase inhibitor and monovalent degrader of the mutant p110α catalytic subunit of mutant PI3Kα. The molecule selectively depletes mutant p110α in cancer cells with active receptor tyrosine kinase (RTK) signaling, and is in several ongoing or planned Ph. III trials for breast cancer. Recently, Genentech announced Ph. III results with the molecule showing that it could be a best-in-class treatment option for PI3Kα-driven cancers. This article explains how it works, how it was discovered, and why it matters.

Toward an oral, once-daily non-peptide STT2 agonist. Paltusotine a novel oral somatostatin receptor 2 (SST2) agonist and Crinetics’ lead investigational drug, is intended to treat acromegaly and neuroendocrine tumors (NETs) in carcinoid syndrome. Both diseases have been treated with surgery and injectable somatostatin [...]

What is it? Compound 49 is an orally available CD73 inhibitor with dose-dependent PK/PD and an immune-mediated antitumor mechanism of action. The molecule is highly potent in human plasma (0.38 nM), and despite having a high free fraction (42% unbound) and possessing several highly polar or charged groups, rings, hydrogen bond acceptors and [...]

Futibatinib (Lytgobi) is a rare alkyne-containing, irreversible FGFR1-4 inhibitor that received accelerated approval from the FDA in September 2022. Structurally distinct from other approved FGFR2/3 inhibitors, futibatinib treats a range of FGFR-aberrant tumors, including those with fusions or TKI-resistant mutants like the V565I/L gatekeeper [...]

A first-in-class diazo-prodrug for the treatment of solid tumors. Sirpiglenastat (DRP-104) (Johns Hopkins/Dracen Pharmaceuticals) is a dual prodrug of 6-diazo-5-oxo-l-norleucine (DON), a diazoketone-based glutamine irreversible antagonist used to suppress cancer cell metabolism. Rapidly growing cancer cells depend on glutamine as an energy [...]

The first approved EGFR exon 20 mutant inhibitor. While there are now three generations of EGFR inhibitors approved, patients harboring the common EGFR exon 20 insertion resistance mutations haven’t responded well to previously approved drugs. This mutation class makes up 4-12% of all mutant EGFR-positive NSCLC cases and has the highest [...]

Overcoming FGFR mutation resistance and FGFR1-mediated hyperphosphatemia toxicity through isoform-selective FGFR2/3 inhibition. “Compound 29” is an ATP-competitive fibroblast growth factor receptor (FGFR) 2/3 inhibitor with subnanomolar potency. FGFR is a receptor tyrosine kinase (RTK) involved in cell differentiation, proliferation [...]

Toward CTPS1 inhibitors as a safer alternative to nucleoside chemotherapeutics: Rapidly growing cancer cells are critically dependent on synthesis of nucleotides, the building blocks of RNA and DNA. Blocking the synthesis of nucleotides is a tried-and-true mechanism of action for widely used chemotherapeutics such as cytarabine (ara-C) and [...]

WASp as a new target for hematological cancers. Wiskott-Aldrich syndrome protein ( WASp ) is a protein almost exclusively expressed in hematopoetic cells that promotes actin polymerization. The WAS gene plays an important but not fully understood role in human immune cell biology, illustrated by WASp deletion in B-cells inducing autoimmunity [...]

In 2022, Turning Point Therapeutics ($TPTX) was acquired by BMS for a whopping $4.1 billion in cash. In November 2023, the most advanced molecule from Turning Point, repotrectinib, was approved for the treatment of ROS1+ NSCLC. This article explores the science behind repotrectinib, what made Turning Point so valuable, how we know, and what's next. [...]

Context. “ Compound 57 ” (Roche) is an oral allosteric EGFR L858R inhibitor being developed for NSCLC. Drug resistance and associated disease relapse continue to remain unmet needs for patients with NSCLC tumors harboring EGFR mutations, despite the availability of three generations of TKIs for EGFR+ NSCLC. Although the widely used [...]

Context. BI-0474 (Boehringer Ingelheim) is a covalent KRAS G12C inhibitor. KRAS continues to be a hotly pursued oncotarget since the first report by the Shokat group of the druggability of the KRAS G12C mutant. Recently, Amgen’s first-in-class sotorasib (Lumakras) was approved, while Mirati Therapeutics’ adagrasib (MRTX84) may be approved in [...]

Context. “ Compound 5g ” (Incyte) is a selective cyclin-dependent kinase 2 (CDK2) inhibitor. Although CDK2 is a highly pursued cancer drug target , inhibitors targeting the key cell cycle regulator have not enjoyed similar success as CDK4/6 inhibitors , in part due to the major challenge of mitigating off-target CDK1/9 activity through the [...]

Context. JNJ-64264681 (Janssen) is a covalent Bruton’s tyrosine kinase (BTK) inhibitor being developed for hematological malignancies. The first-in-class irreversible BTKi ( ibrutinib ) was approved in 2013, while many others have been approved or are in clinical development with potentially reduced off-target effects . We recently covered [...]

Context. BAY-069 (Bayer) is a branched-chain amino acid transaminase (BCAT) 1/2 inhibitor. Involved in the synthesis and breakdown of branched-chain amino acids, BCAT1 and BCAT2 have also been implicated in several diseases, including various cancer types, with the ligandability evidenced by the many reported inhibitors . Tool compound [...]

PI3 kinases are part of the PI3K/Akt/mTOR signaling pathway that is downstream of Receptor Tyrosine Kinases (RTKs), G-protein-coupled receptors (GPCR), and GTPases such as KRAS. Since their identification in the 1980s, and due to their central role in cancer, the therapeutic targeting of the phosphatidylinositol-3-kinase (PI3K), and more [...]

Context. AZD1390 (recently published on by University of Minnesota) is a brain-penetrating Ataxia-Telangiectasia Mutated (ATM) kinase inhibitor under development for brain tumors. The kinase, known for its critical role in the repair of lethal DNA lesions induced by radiotherapy treatment, is considered an attractive target for CNS tumors [...]

Context. “Compound 39 ” (RAPT Therapeutics) is a general control nonderepressible 2 (GCN2) protein kinase inhibitor. As the master regulator of the integrated stress response triggered by cellular stress in the tumor microenvironment, GCN2 has been implicated in tumor progression and immune escape, making the kinase an attractive oncotarget [...]

Context. Ziftomenib (KO-539; UMich) is an oral menin inhibitor being developed for mixed-lineage leukemia 1 (MLL1)-rearranged or NPM1 -mutated acute myeloid leukemia (AML). Although a tumor suppressor in endocrine glands, the scaffold protein menin is an essential cofactor for leukemogenesis in leukemia subsets driven by the rearrangement of [...]

Context. GB1211 (Galecto Biotech) is an oral galectin-3 inhibitor under development for fibrotic disease. First described in 1971, galectin-3 , a unique subtype of a 15-member family of carbohydrate-binding proteins, has been implicated in a host of different diseases, such as cancer, liver cirrhosis, and atherosclerosis. Incredibly, over [...]

Context. CH7057288 (Chugai Pharmaceutical Co) is an oral pan-tropomyosin receptor kinase (TRK) inhibitor. Chromosomal rearrangements in the NTRK1–3 genes that encode gene fusions leading to TRK fusion proteins have been shown to drive oncogenesis in many human tumors. Several inhibitors targeting kinase fusions have been developed and are [...]

Context. GNE-064 (Genentech) is an oral inhibitor of the bromodomains of SMARCA2/4 and PBRM1 being developed as a tool compound. Many proteins contain bromodomains (there are 61 in the human genome), which recognize acetyl lysines and are involved in regulating gene transcription. Proteins that contain bromodomains are often mutated in [...]

Context. “ Compound 6 ” (Novartis) is a first-in-class YAP-TEAD protein-protein inhibitor. The TEAD transcription factor and its coactivator YAP and WWTR1/TAZ of the Hippo pathway are responsible for directly regulating the expression of genes involved in cell proliferation and organ size. Several kinases in the cascade have recently gained [...]

“Compound 3” (UCSF) is a covalent KRAS G12R inhibitor used as a proof-of-concept for covalent arginine modification. KRAS is the first oncoprotein to be identified and is a well-known cancer-driving protein. As one of the most frequently mutated proteins in pancreatic and colorectal cancers, residues that are frequently mutated are [...]

Context. “ Compound 19 ” (Janssen) is an oral dihydroorotate dehydrogenase (DHODH) inhibitor being developed for acute myelogenous leukemia (AML). DHODH is a ubiquitously expressed, essential enzyme in the de novo pyrimidine biosynthesis pathway. Despite its ubiquitous expression and lack of known mutations or overexpression in cancer, DHODH [...]

Context. BI-4142 (Boehringer Ingelheim) is a HER2 exon 20 insertion mutant inhibitor being developed for non-small cell lung cancer (NSCLC). Despite the general advances made in HER2-targeted therapy and the existence of several agents targeting HER2-positive breast cancer , a high unmet need exists for patients with HER2 mutant NSCLC [...]

Context. MRTX0902 (Mirati Therapeutics) is an oral brain penetrating SOS1:KRAS protein-protein interaction inhibitor. Since the first report of the druggability of the KRAS G12C mutant, KRAS has been a hotly pursued oncotarget. Notably, the first-in-class sotorasib (Lumakras; Amgen) was recently approved, while Mirati Therapeutics’ highly [...]

Context. RP-6306 is an oral protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1) Inhibitor being developed for various solid tumors. PKMYT1, together with WEE1, make up the WEE family of serine/threonine kinases, which have been implicated in the progression of several cancers, especially solid tumors . At least 4 WEE1 inhibitors [...]

Context. BLU-945 (Blueprint Medicines) is an oral EGFR mutant inhibitor being developed for treatment-resistant non-small-cell lung cancer (NSCLC). Although three generations of EGFR TKIs are available for EGFR -mutant NSCLC, drug resistance and associated disease relapse are still highly prevalent. The widely used third-generation agent [...]

Context. EZM0414 (Epizyme, Inc.) is an oral SETD2 inhibitor being developed for hematological malignancies . Although several genetic studies have proposed that the histone methyltransferase SETD2 is a tumor suppressor in solid cancers, inhibition of the enzyme may be desirable in some hematological malignancies such as leukemia and lymphoma. [...]

Context. TAS1553 (Taiho Pharmaceutical) is an oral ribonucleotide reductase (RNR) inhibitor with antitumor activity . As the enzyme that catalyzes the rate-limiting step for deoxyribonucleotide triphosphate (dNTP) synthesis in cells, RNR has long been of interest to anticancer drug discovery efforts, especially since unlimited dNTP supply is [...]

Context. NTQ1062 (Nanjing Chia-Tai Tianqing; CTTQ) is an oral ATP-competitive Akt inhibitor being developed for cancer . Because the PI3K/Akt/mTOR pathway is one of the most commonly disrupted pathways in cancer, inhibitors targeting one or more of the three kinases have been hotly pursued. To date, five PI3K and three mTOR inhibitors have [...]

This short article and poster summary takes a deeper look into the 2021 IPOs for biotechnology-based therapeutics being developed by oncology-focused companies, including: Antibody-drug conjugates Monoclonal antibodies Protein-based therapeutics Cell and gene therapies Other biotechnology-based therapeutics This article is Part 4 of a review [...]

This article is Part 3 of a review series covering all of the initial public offerings for the biotech and pharmaceutical industries in 2021. Part 1 provided an overview of 2021 IPOs by therapy area, technology, and therapeutic class. Part 2 provided an overview of 2021 IPOs by therapeutic area. This short article takes a deeper look into the [...]

Context. Pevonedistat (Takeda) is a first-in-class intravenous or subcutaneous NEDD8-activating enzyme (NAE) inhibitor being developed for leukemia and advanced solid tumors. NAE is a pivotal regulator of the NEDD8 conjugation pathway which regulates the activity of the Cullin-RING ligases (CRLs), key proteins involved in the [...]

NVP-CLR457 (Novartis Institutes for BioMedical Research) is an oral, non-CNS-penetrating pan-class IA phosphoinositide 3-kinase (PI3K) inhibitor . Due to the key involvement of PI3K in the famed PI3K-Akt−mTOR pathway, whose deregulation has been observed in several cancers , it is no surprise that the last decade has seen over 600 [...]

Context. ”Compound 53” (University of Texas Southwestern Medical Center) is a stimulator of interferon (IFN) genes (STING) agonist . STING agonists have been heavily pursued in cancer immunology as increasing data suggests that the efficacy of immunotherapy can be enhanced by proteins such as STING that can induce a strong innate immune [...]

Context. JDQ443 (Novartis Institute for Biomedical Research) is an oral KRAS^G12C inhibitor being developed for various advanced solid tumors . Despite accounting for 85% of RAS oncogenic mutations in all cancers, KRAS was considered undruggable until 2013 when a report describing the targetability of the KRAS^G12C mutant by small molecule [...]

Context. AZD4625 (AstraZeneca) is an oral inhibitor of KRAS G12C being developed for the treatment of advanced solid malignancies . As indicated for JDQ443, the KRAS G12C mutation presents the perfect “Achilles heel” for targeting a KRAS protein previously thought undruggable. The protein is a current hot topic in precision oncology , with [...]

Context. “ Compound 41” (Vanderbilt University School of Medicine) is an oral WD40 Repeat Domain 5 (WDR5) inhibitor being developed for various human cancers . The well-established role of epigenetic abnormalities in cancer development and progression has led to extensive studies to identify various epigenetic cancer inhibitors. Currently [...]

JBJ-09-063 (Dana-Farber Cancer Institute) is an oral allosteric EGFR inhibitor currently in pre-clinical development for the treatment of EGFR L858R -mutant non-small cell lung cancer (NSCLC) . Despite the availability of 3 generations of EGFR TKIs for the treatment of EGFR-mutant NSCLC, drug resistance and associated disease [...]

Momelotinib, an oral JAK1/2 inhibitor for myelofibrosis, is going to GSK as part of a $1.9 billion acquisition of Sierra Oncology. Anyone that’s ever worked on a kinase program probably looked at this structure and raised their eyebrows. $1.9 billion for another JAK2 inhibitor? It’s probably not super selective either, you might think… and [...]

MK-1454 (Merck) is an intratumoral stimulator of interferon (IFN) genes (STING) agonist that is being developed for treatment of advanced solid tumors and lymphomas. The molecule follows Aduro’s ADU-S100 , which was terminated after Ph. II due to a lack of substantial activity. Another chemotype of STING agonist, Eisai’s E7766 , has [...]

Context. “ Compound 24” (Amgen) is a kinesin-like protein 18A (KIF18A) inhibitor being developed for a subset of cancers with chromosomally unstable tumor cells . Their first-in-class, oral clinical candidate, AMG 650, was recently disclosed at ACS Spring 2022 and is in Ph. I for cancer. Both antimitotic drugs targeting microtubules and those [...]

Context. MAK683 is an oral, allosteric and selective PRC2 inhibitor intended for PRC2-dependent cancers . PRC2 is an essential epigenetic regulator of gene expression and enhanced or diminished PRC2 function have been implicated in a number of cancers . Enhancer of zeste homolog 2 (EZH2), one of the four core components of PRC2 that directly [...]

There were six small molecule candidates disclosed on Apr. 10th at AACR New Orleans 2022 at the New Drugs on the Horizon session, with another four on Apr. 11th. The New Drugs on the Horizon session is organized by the Chemistry in Cancer Research (CICR) Working Group , this year chaired by Joachim Rudolph . Thanks to reviewer Julien Lefranc [...]

This article reviews the three novel drugs approved by the FDA in March 2022 in detail. together with Dr. Naveed Yasin, Jesse Keicher, Dr. Jennifer Huen, and Dr. Adrian Parodi Small molecules: Ztalmy ® ( ganaxolone ): An oral GABAA receptor positive allosteric modulator to treat seizures in cyclin-dependent kinase-like 5 deficiency disorder [...]

Context. ASP5878 (Astellas Pharma Inc.) is an oral pan-FGFR inhibitor. The four FGFRs have emerged as attractive targets for cancer in recent years, and we’ve covered several recently. FGFR3 has had less dedicated effort disclosed on it specifically relative to FGFRs 1, 2, and 4, but genetic alterations of FGFR3 have been noted in bladder [...]

AZ13824374 (AstraZeneca) is an in vitro ATAD2 inhibitor. Reviewer and nominator Julien Lefranc says, “several ATAD2 probes have been published in the past (including GSK 8814, GSCK388, and BAY-850), but so far no compounds have reached clinical trials.” ATAD2 is a bromodomain-containing, chromatin-binding target that is overexpressed [...]

Context. AZD7648 (AstraZeneca) is an oral DNA-PK inhibitor. DNA-PK, ATR, and ATM are all kinases involved in DNA damage repair and have been of significant recent interest due to the success of PARP inhibitors and the concept of synthetic lethality. We have highlighted a few DNA-PK inhibitors and ATR inhibitors recently. The discovery of [...]

Context. MAP855 (Novartis Institutes for BioMedical Research) is an oral MEK1/2 active-site inhibitor. Several MEK inhibitors (e.g. cobimetinib, trametinib) have been approved for cancer, generally derived from the same allosteric pharmacophore. MEK inhibitors continue to be explored in combination with new drug mechanisms, with recent [...]

This article reviews the novel drugs approved by the FDA in February 2022. together with Dr. Naveed Yasin, Dr. Vinicius Texeira, and Dr. Jennifer Huen Three novel molecules were approved in February 2022: Small molecules: Pyrukynd (mitapivat) : An oral pyruvate kinase activator approved for the treatment of hemolytic anemia in adults with [...]

together with Dr. Jennifer Huen, Saumil Patel, and Dr. Naveed Yasin In 2021, the FDA approved 9 non-radiological novel small molecule drugs for oncology. Excluding melphalan flufenamide, which has already been withdrawn, the remaining FDA-approved novel small molecule oncology drugs of 2021 are: umbralisib (PI3Kδ and CK1ε inhibitor) sotorasib [...]

MRTX1719 is PRMT5-MTA complex inhibitor for the treatment of MTAP-deleted cancers currently in IND-enabling studies. PRMT5 is a target of active interest with several molecules recently highlighted here . Inhibition of PRMT5 is expected to induce synthetic lethality in MTAP-deleted tumors – however, PRMT5 is also an essential gene for [...]

MIW815 (ADU-S100) is a first-in-class STING agonist for cancer immunotherapy. Agonism of the STING (stimulator of IFN genes) receptor, true to its name, leads to stimulation of type I IFN production , aiding the antitumor immune response. Systemic activation of STING, however, may lead to negative immunologic effects such as cytokine storm [...]

The ARIAD/Takeda EGFR exon 20 insertion mutant (EGFRex20ins) inhibitor TAK-788 is a Breakthrough Therapy for patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 20 insertion mutations.  The appearance of exon 20 insertions is a common resistance mechanism to earlier generations of EGFR inhibitors including [...]

The Genentech PI3Kα isoform-selective kinase inhibitor and mutant PI3Kα degrader inavolisib selectively depletes the oncogenic mutant p110α catalytic subunit of PI3Kα in cancer cells with active receptor tyrosine kinase (RTK) signaling. The gene encoding p110α, PIK3CA, is one of the most frequently mutated oncogenes, with over 2M cancer [...]

MRTX1133 was nominated as December 2021’s cover molecule by reviewers Joachim Rudolph and Julien Lefranc . MRTX1133 is a non-covalent inhibitor of KRASG12D that demonstrated tumor regression in a mouse xenograft model when dosed IP (maximum efficacy at 10-30 mg/kg, activity as low as 3 mg/kg). Joachim said, “The discovery of MRTX1133 deserves [...]

The Arvinas ER chimeric degrader, ARV-471 , is an oral, bioavailable ER degrading CRBN-based  PROTAC for the treatment of patients with ER+/HER2- breast cancer. Along with ARV-110 , it is one of the first chimeric degraders to enter a Ph. II clinical trial. It was first disclosed at AACR in early 2021, and though the molecules have not been [...]

The Kronos CDK9 inhibitor, KB-0742, is an ultraselective inhibitor of cyclin-dependent kinase CDK9. The CDK family of kinases have been pursued as cancer drug targets for decades, but family selectivity within the highly conserved kinase family has made it difficult to identify highly selective molecules, resulting in less than ideal [...]

The Revolution Medicines KRASG12C inhibitor, RM-018, “glues” KRASG12C to the highly abundant chaperone protein, cyclophilin A, in a tri-complex (KRAS- inhibitor-cyclophilin A) stabilized by protein-protein interactions. An undisclosed molecule in their pipeline with a related mechanism, RMC-6291 , has been reported to be orally bioavailable [...]

The H3 Biomedicine RNA splicing modulator, H3B-8800 , targets the spliceosome SF3b complex containing either wild-type (WT) or mutant SF3B1. Splicesome inhibition can induce synthetic lethality since cancer cells bearing spliceosome mutations are more dependent on WT spliceosome function. The compound is derived from the natural product [...]

In Aug. 2021, immuno-oncology company, Trillium Therapeutics, was acquired by Pfizer for $2.3 billion , adding Trillium’s two CD47-targeting biologics, TTI-621 and TTI-622, to Pfizer’s oncology pipeline. The acquisition followed Gilead’s $4.9B buyout of Forty Seven in early 2020, after clinical data was presented on Forty Seven’s lead, the [...]

The global cancer immunotherapy pipeline continues to explode with nearly double the number of active targets in 2019 vs. only two years ago, comprising 3,876(!!) active drugs, with a subset undergoing >5000 active clinical trials. In 2016, I listened to Dan Chen, former Global Head of Cancer Immunotherapy Development at Genentech, comment on [...]

Checkpoint inhibitors like pembrolizumab (Keytruda) have revolutionized treatment for many late-stage cancer patients, including Jimmy Carter. Recently, Keytruda stunned the world again with efficacy in metastatic non-small cell lung cancer, the leading cancer killer. Here's a summary of its recent successes and the surprising path Keytruda [...]

Gleevec (imatinib) was the first tyrosine kinase inhibitor approved for the treatment of cancer and one of the first products to emerge from "rational drug design."  It's invention changed chronic myeloid leukemia from an incurable death sentence to a manageable disease. Here's a look back on the tremendous value it's created over the last [...]