Lew Pennington

Tyra Biosciences’ lead asset, TYRA-300, is a potent, selective, and orally bioavailable FGFR3 inhibitor designed to mitigate the toxicities commonly seen with pan-FGFR inhibitors. A key objective of the program was to meet the safety standards required for advancing into pediatric populations for the treatment of ACH (achondroplasia) and other skeletal dysplasias. TYRA-300 is currently being evaluated in Ph. I clinical trials for advanced urothelial cancers and other solid tumors and, importantly, has received IND clearance to initiate a Ph. II clinical trial in pediatric ACH patients.

GSK and Roche strengthened their pipelines by forming groundbreaking collaborations that target neurodegenerative diseases and transcription factors, respectively. Meanwhile, Pep2Tango Therapeutics introduced a novel obesity treatment approach, and Amgen faced scrutiny over emerging data on its obesity drug candidate MariTide. This roundup covers the details behind these headlines.

This summary of major clinical updates from November 2024 covers FDA approvals, the initiation of new clinical trials, notable trial outcomes for key drug candidates, and news on paused and discontinued trials and programs.

HRX-215 is an orally bioavailable MKK4 inhibitor for liver regeneration. In just over a decade since they discovered the dual specific kinase MKK4 as a master regulator of hepatocyte regeneration, HRX-215 completed a FIH clinical trial. This article is a fascinating case study on harnessing the liver's natural regenerative capacity, identifying key regulators of liver regeneration, and leveraging a kinase inhibitor with reported off-target activity for MKK4 as a suitable starting point, among other insights.

Our October patent highlights cover a diverse array of drug discovery IP disclosures. From piperidine-based USP19 inhibitors and small molecule GIPR antagonists for obesity to KCC2 potentiators for epilepsy, the month delivered a number of exciting IP developments. Other notable discoveries include MTA-cooperative PRMT5 inhibitors, direct-acting influenza antivirals against a novel target, Nrf2 activators for heart failure, and a slew of Polθ inhibitors for HR-deficient cancers.

IAG933 is Novartis’ potential first-in-class small molecule inhibitor of the PPI between YAP/TAZ and TEAD, currently in a Ph. I trial for solid tumors with Hippo pathway alterations. This case study not only highlights a fascinating mechanism of action but also serves as an excellent example of how to leverage structural data to inform hit selection and guide lead optimization, how to employ multiparameter optimization to circumvent cardiotoxicity liabilities, and how to redirect metabolism.

In this roundup, we present a curated selection of over 50 molecules from October that captured our team’s interest. We highlight our top picks and offer insights into what makes them stand out.

Morphic Therapeutic’s MORF-627 is an oral αvβ6 integrin inhibitor designed to treat IPF by blocking the TGFβ pathway. The Morphic team leveraged SBDD and FEP+ during lead optimization to enhance permeability and isoform selectivity. This article highlights the team’s focus on inhibiting the “bent-closed” conformation of αvβ6 as well as the linker design that led to the “chameloenicity” of the lead compound. The impressive multispecies PK and in vivo efficacy of MORF-627 in preclinical models was unfortunately accompanied by oncogenic toxicity that prevented it from reaching clinical trials.

Medicinal chemists often face cardiotoxicity issues linked to inhibition of the hERG (human ether-à-go-go-related gene) channel. In a recent Coffee Chat, Drug Hunter CEO Dennis Hu, Director for Industry Research and Relations Dennis Koester, and Senior Scientific Editor Matt Hesse discussed ways to reduce hERG risks during lead optimization. They described approaches to reduce hERG affinity while retaining on-target potency and discussed case studies of drug programs that used these strategies to eliminate their hERG issues.

The 2024 edition of MCR (Medicinal Chemistry Reviews), edited by Joachim Rudolph and Will Watkins, has just been published by the American Chemical Society MEDI Division. Featuring contributions from a global team of section editors and authors, MCR offers concise updates on a broad range of contemporary drug discovery topics, making it an invaluable resource for both aspiring and experienced medicinal chemists.

Nurix’s NX-2127 is an orally bioavailable BTK degrader that exhibits in vivo degradation across species and has advanced into first-in-human clinical trials for relapsed/​refractory B-cell malignancies. This molecule one-pager serves as a reference guide, offering an overview of the scientific significance of Nurix's NX-2127 program. It includes links to key presentations, publications, patents, preclinical and clinical PK data summaries, and more.

Chiesi Farmaceutici’s CHF-6523 is an inhaled, lung-restricted, selective PI3Kδ inhibitor designed to provide relief to patients with COPD. Its development involved optimization of permeability and solubility as well as identification of a solid form amenable for dry powder inhalation. Disclosed at the EFMC-ISMC 2024 joint conference in Rome, Italy, this article covers the structure, development, and early clinical data of CHF-6523, which ultimately indicates that PI3Kδ inhibition may not provide clinical effect in reduction of lung inflammation.

AZ-PRMT5i-1 is an orally bioavailable MTA-cooperative PRMT5 inhibitor that specifically targets MTAP-deleted cancers and is structurally related to AZ’s clinical candidate, AZ3470. This case study is an excellent example of utilizing bioisosteric replacements for polar guanidine headgroups, rigidifying scaffolds through spirocyclization to reduce rotatable bonds, and leveraging fluorine atoms beyond simply blocking metabolic soft spots.

BAY 2413555 is a M2R PAM that has the potential to counter parasympathetic withdrawal and restore autonomic balance in heart failure patients. The preclinical and clinical data of BAY 2413555 showed it has positive effects on heart rate and heart rate variability and a relatively long human t1/2 of 37 h. The Ph. I trial, however, was terminated in March 2024 due to findings from a chronic toxicology study. This article covers the discovery of BAY 2413555, presented by Alexandros Vakalopoulos of Bayer at the EFMC-ISMC 2024 conference in Rome and published in the Journal of Medicinal Chemistry.

This October roundup features key clinical updates, including FDA approvals, significant trial results for major drug candidates, the initiation of new clinical trials, and updates on halted studies.

CDI (Clostridioides difficile) infection is a leading cause of healthcare-associated diarrhea with significant morbidity and mortality, and with the rise of hypervirulent and resistant strains, novel and selective antibiotics to treat these infections are needed. Cadazolid, a hybrid antibiotic that combines pharmacophores of two classes of antibacterials, demonstrated potent activity in vitro against relevant C. difficile strains, while avoiding native gut flora. Additionally, the compound was designed to be gut-restricted, with minimal systemic circulation following PO dosing.

Sonrotoclax, BeiGene’s clinical-stage, orally bioavailable, next-generation inhibitor, targets both WT and mutated forms of the Bcl-2 protein by binding within a hydrophobic groove, similar to other inhibitors in its class. Explore this case study to see how sonrotoclax was rationally designed to potency against both WT and mutant Bcl-2 and address the limitations of first-generation inhibitors and more!

Here’s a quick recap of the top business news from October, including major deals, acquisitions, funding rounds, and strategic partnerships. If you missed any updates, here’s your chance to catch up on the most significant developments in the industry.

This article highlights key patents published in September 2024, covering a range of therapeutic targets and mechanisms. It includes Nurr1 and Nur77 modulators for oncology applications, STAT3 inhibitors and CRBN-based STAT3 degraders for modulating STAT3 signaling in cancer, and CDK2 molecular glue degraders for estrogen receptor-positive breast cancer resistant to CDK4/CDK6 inhibitors. Additionally, it features ERAP1 modulators for addressing autoimmune diseases, APOL1 inhibitors for APOL1-mediated kidney diseases, and novel NEK7 inhibitors targeting the NLRP3 inflammasome pathway.

HiberCell recently disclosed the discovery of HC-7366, a potential first-in-class, intentionally discovered, orally bioavailable, potent, selective, small-molecule kinase activator of GCN2. HC-7366 has now progressed to Ph. I trials to treat ccRCC and AML. This case study is a fantastic example of how to mitigate CYP3A4 inhibition and improve oral bioavailability via judicious choice of salt formulation.

Novartis' NLRP3 inhibitor, NVP-DFV890, features a unique sulfonimidamide motif designed to reduce hydrolysis relative to traditional sulfonylureas. This potent compound, with promising PK in humans, is advancing through multiple clinical studies, including Ph. II trials for coronary heart disease and knee osteoarthritis. Presented by Angela Mackay at the EFMC-ISMC 2024 joint conference in Rome, this overview covers NVP-DFV890's discovery, as well as its preclinical PK and PD data.

In this article, we present a curated selection of over 60 molecules from September that caught our attention, along with highlights of our top picks and insights into why they stand out.

Recently, a surge of (pre)clinical compounds inhibiting the NLRP3 inflammasome, often featuring a hexahydroindacene ring system, has emerged, including Nodthera’s ND-0796. In a push for new chemotypes, AZ and Mitsubishi Tanabe have disclosed their clinical compound, AZD4144, which is currently in Ph. I trials in healthy volunteers. The discovery story detailed their efforts to overcome PLD (phospholipidosis), genotoxicity, and hERG inhibition in a non-classical pharmacophore series. The discovery was presented by Anders Johansson at the EFMC-ISMC 2024 Meeting in Rome.

Infection with the malaria parasite, Plasmodium falciparum, is a leading cause of fatality in the tropical regions of the world, with >240M infections and >600K deaths each year, the majority of which are in sub-Saharan Africa. The need for new antimalarials is clear, given that over half of the world's population is at risk of infection, combined with the rise of resistance against current treatments. Novartis has played a key role in this fight and at the ACS Fall 2024 meeting in Denver, CO, they disclosed NVP-FVP954: a novel, fast-acting IV antimalarial for severe malaria.

Sovleplenib (HMPL-523) is an orally bioavailable Syk inhibitor being developed by HUTCHMED and is currently in Ph. II and Ph. III clinical trials for several autoimmune diseases. Derived from an HTS hit and SAR optimization, the discovery story of sovleplenib serves as an excellent case study on how to design a next-generation Syk inhibitor devoid of off-target kinase activity, mitigated hERG activity, and more.

BMS-986397 is a potential first-in-class CRBN-based selective CK1α molecular glue degrader. CK1α promotes tumor growth by enhancing MDM2 and MDMX degradation of the tumor suppressor p53. Since AML has a low TP53 mutation rate, activating the p53 pathway is a promising approach; however, p53 activators have faced challenges due to hematological toxicities. Targeting CK1α degradation offers an alternative approach. The BMS team sought to develop a CELMoD® for CK1α degradation. This article outlines the discovery of BMS-986397, as presented at the ACS Fall 2024 meeting in Denver, CO.

EOS-984 is an oral, potential first-in-class, highly selective ENT1 inhibitor from iTeos currently in clinical trials for advanced solid tumors. The drug, which was identified through SBDD and optimization of the vasodilator dilazep, targets the immunosuppressive effects of adenosine, which helps tumors evade immune detection. This is an excellent case study on the importance of understanding a molecule's bioactive conformation to reduce the entropy of binding and enhance potency.

Despite the remarkable emergence of HAART in the 1990s, the fight against HIV infection is by no means finished. At the ACS Fall 2024 meeting in Denver, CO, Gilead Sciences presented the structure and discovery story of elunonavir (GS-1156), a novel HIV protease inhibitor with remarkable metabolic stability and a human half-life exceeding two weeks. Based on BMS’ atazanavir, the compound incorporates structural elements inspired by Gilead’s HCV NS5A inhibitor program which led to ledipasvir, as “stabilizer” motifs to avoid the extensive CYP metabolism seen in current inhibitors.

BMS-986408 is an oral, dual DGK ⍺ and ζ inhibitor currently in a Ph. I/II trial in patients with solid tumors. The compound was identified stemming from a phenotypic screening approach, and subsequent target deconvolution revealed DGK to be the target. If approved, it would be a first-in-class intracellular checkpoint inhibitor of DGK. This is an excellent case study on how to overcome a DILI risk associated with BSEP inhibition, as well as how to improve solubility and PK properties of your compounds through the introduction of polarity, reduction of aromatic rings, and increase in f(sp3).

Arvinas’ ARV-471 is an orally bioavailable CRBN-based ER PROTAC degrader for treating patients with ER+/HER2-breast cancer and the first PROTAC to enter Ph. III clinical trials. This molecule one-pager serves as a reference guide, offering an overview of the scientific significance of Arvinas’ ARV-471 program. It includes links to key presentations, publications, patents, preclinical and clinical PK data summaries, and more.

This summary of September's major clinical updates features FDA approvals, drug withdrawals, anticipated regulatory decisions, notable trial results, new NDA submissions, clinical trial setbacks, and the initiation of new clinical trials.

In this article, you'll find a curated selection of >70 molecules from August that piqued our interest, highlights of some of our favorites, and explanations of why they're worth watching.

This article highlights the key drug discovery patents published in August 2024, including AKR1C3-dependent KARS (not KRAS!) inhibitors for NRF2/KEAP1-mutated cancers and DHX9 helicase inhibitors of MSI-high tumors. It also covers the development of MK2 degraders for inflammatory diseases and small molecule IL-17A inhibitors that show promise in modulating inflammation. Additionally, we cover Roche’s take on Revolution Medicines’ macrocyclic pan-KRAS inhibitors, which show improved PK profiles, and novel non-hydroxamate LpxC inhibitors for treating Gram-negative bacterial infections.

KEAP1 inhibition/NRF2 activation has been hotly pursued in recent years for immunology indications; however, in oncology, NRF2 degradation has been posited as a novel therapeutic mechanism for specific cancers. Vividion has already disclosed work on covalent KEAP1 inhibitors, but at the recent ACS Fall 2024 meeting, the structure and discovery story of their clinical oral covalent activator of KEAP1 were disclosed, identified through careful analysis of the data from their inhibitor screen.

Arvinas’ ARV-393 is an orally bioavailable PROTAC that degrades BCL6 via CRBN-mediated ubiquitination and proteasomal degradation intended for the treatment of NHL. At the AACR San Diego 2024 meeting, Arvinas disclosed the structure and discovery story of this molecule, which exhibits first-in-class potential. This article covers the key SAR observations that led to the invention of this orally bioavailable PROTAC®, its performance in a triple-hit, high-grade BCL and R-CHOP-resistant cell line, and why sustaining BCL6 knockdown beyond 24 hours was critical for the success of this program.

During Drug Hunter’s Flash Talks, experts talk in-depth about hot topics in drug discovery. These experts also share insights beyond the subjects of their presentations, such as how they got inspired to become a drug hunter, what their favorite molecule is, what excites them most in drug discovery today, and what advice they wish they could give their younger selves. Here is a quick look at some of these insightful nuggets from Flash Talks hosted between January and August 2024.

This article highlights a patent application from Monte Rosa Therapeutics that discloses the biological activity of compounds that act as VAV1 molecular glue degraders, providing a summary of key data for selected molecules disclosed in the patent application.

In case you missed August’s business news, here’s a quick recap of five headlines, including an acquisition, three funding rounds, and a notable company closure.

Here’s a rundown of August’s key clinical developments, including FDA approvals, potential upcoming approvals, notable trial readouts, new NDA submissions, and pipeline realignments.

This article highlights a patent application from Constellation Pharmaceuticals that discloses the biological activity of compounds that act as TREX1 inhibitors, providing a summary of key data for selected molecules disclosed in the patent application.

This article highlights a patent application from AstraZeneca and Mitsubishi Tanabe, and Astellas Pharma that discloses the biological activity of compounds that act as NLRP3 inhibitors, providing a summary of key data for selected molecules disclosed in the patent application.

This article highlights a patent application from Arvinas that discloses the biological activity of compounds that act as tau-targeting heterobifunctional degraders, providing a summary of key data for selected molecules disclosed in the patent application.

This article highlights a patent application from Puhe BioPharma that discloses the biological activity of compounds that act as WRN helicase inhibitors, providing a summary of key data for selected molecules disclosed in the patent application.

The highly anticipated First Time Disclosures session, attended by over 400 conferees, both in-person and virtually, was organized by the MEDI Division of ACS at the ACS Fall 2024 meeting in Denver. This session unveiled 13 fascinating small molecules currently in clinical development. The two-part event showcased innovations ranging from Novartis’ pentafluorosulfanyl-containing antimalarial, IWY357, to Vividion’s covalent activator of KEAP1, which targets NRF2 degradation. This article captures the essence of the session, providing the structures and targets of the novel molecules disclosed.

Kymera's KT-474 is the first oral heterobifunctional degrader to demonstrate activity in clinical trials outside cancer. This molecule one-pager serves as a reference guide, offering an overview of the scientific significance of Kymera's KT-474 program. It includes links to key presentations, publications, patents, preclinical and clinical PK data summaries, and more.

Minipigs have recently gained prominence as an alternative non-rodent in vivo model for pharmacokinetic (PK), efficacy, and toxicology studies supporting human dose predictions. This article provides an overview of the use of minipigs in small molecule preclinical drug discovery research, tracing their historical background and outlining practical considerations for selecting them in studies focusing on hepatic metabolism, oral bioavailability, CNS penetration, and toxicology. It highlights minipigs' unique advantages and makes a compelling case for their continued use in preclinical research.