An Unexpected Sotorasib Setback Creates an Opening for KRAS Competitors

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?

Amgen’s first-in-class KRAS(G12C) inhibitor, sotorasib, recently encountered an unexpected but significant regulatory setback with...

Fenebrutinib: A Reversible, CNS-Active BTK Inhibitor for MS

Genentech announced that fenebrutinib (GDC-0853), a non-covalent BTK inhibitor entering Ph. III, showed significant human CNS exposure and reduced new brain lesions in Ph. II for relapsing multiple sclerosis. Fenebrutinib is the only reversible BTK inhibitor in Ph. III for MS, and has the opportunity to differentiate on safety relative to covalent inhibitors. This case study highlights notable challenges overcome in the discovery of fenebrutinib including surprising metabolism, animal-specific on-target toxicity, and more.

Genentech announced that fenebrutinib (GDC-0853), a non-covalent BTK inhibitor entering Ph. III, showed significant human CNS expo...

September 2023

This month features many molecules in Phase III clinical trials including Calcilytix’s CaSR antagonist for hypocalcemia and DalCor Pharma’s repurposed CETP inhibitor to treat cardiovascular disease. We’ll have more detailed case studies on these molecules coming soon, but in the meantime, you can check out some recent articles about the following here: NVL-520 - an oral brain-penetrant ROS1-selective TKI in Phase I/II clinical trials for NSCLC and other solid tumors, designed through rational drug design (SBDD) from a known chemotype. GDC-1971 (RLY-1971) - an oral allosteric SHP2 inhibitor in...

This month features many molecules in Phase III clinical trials including Calcilytix’s CaSR antagonist for hypocalcemia and DalCor...

The Highly Potent and CNS-Active NX-5948 Shows BTK Degradation in Patients

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.

Nurix recently unveiled their second clinical BTK degrader, NX-5948, which is in Ph. Ia/Ib for patients with advanced B-cell malig...

A 1990’s Abbott Candidate Revived by a Biotech for Renal Health

Atrasentan (ABT-627/A-127722) is an ETA receptor antagonist that was originally discovered by Abbott (AbbVie) in the 1990s to treat prostate cancer. Unfortunately, clinical data with the compound in prostate cancer was insufficient for approval, and AbbVie pivoted the compound to chronic kidney diseases instead, ultimately conducting a large, 5,000+ patient trial (SONAR) that was published in 2019.

Atrasentan (ABT-627/A-127722) is an ETA receptor antagonist that was originally discovered by Abbott (AbbVie) in the 1990s to trea...

Welcome to Phase III!

With initial signs of efficacy and tolerability, Drug Hunter has launched Phase III! To address your helpful feedback, we’ve rebuilt the platform from scratch to support new features and enhancements. We appreciate your patience with the rollout!

With initial signs of efficacy and tolerability, Drug Hunter has launched Phase III! To address your helpful feedback, we’ve rebui...

A Next-Generation Mutant-Selective PI3Kα Allosteric Inhibitor with a Potentially Improved Safety Profile

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.

STX-478 is a wild-type-sparing, oral, CNS-penetrant, novel allosteric inhibitor of mutant phosphatidylinositol-3 kinase α (PI3Kα),...

Recent Highlights in Covalent Drug Discovery

In Wednesday’s Flash Talk webinar, we covered recent highlights in covalent drug discovery, with lots of great questions from the audience. The webinar and recording are available below to everyone thanks to our sponsor, Revvity Signals, and the slides are available for download to Premium members at the bottom.

In Wednesday’s Flash Talk webinar, we covered recent highlights in covalent drug discovery, with lots of great questions from the ...

A Clinical, Oral, Cell-Penetrant, Reversible, Macrocyclic Peptide Pan-RAS Inhibitor from mRNA Display

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.

LUNA18 is an orally bioavailable, cell-penetrant, macrocyclic peptide pan-RAS inhibitor (Chugai ’21Q3 earnings call) intended for ...

An Azetidine-Containing, First-in-Class CCR4 Candidate with a 72 h Human Half-life

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

RAPT Therapeutics, formerly known as FLX Bio, was spun out of Flexus Biosciences after its billion-dollar acquisition by BMS for F...

A First-in-Class TRPA1 Antagonist Overcomes Toxicity Hurdles to Become Cough Candidate

Genentech’s GDC-6599 is the first oral TRP Ankyrin 1 (TRPA1) antagonist to reach Ph. IIa (NCT05660850) for chronic cough after preclinical studies and a Ph. I trial showed it was well-tolerated, in contrast to prior molecules. The transient receptor potential (TRP) family of ion channels has been the subject of intensive drug discovery efforts due to their critical role in the development and progression of pain, itch, and respiratory conditions.

Genentech’s GDC-6599 is the first oral TRP Ankyrin 1 (TRPA1) antagonist to reach Ph. IIa (NCT05660850) for chronic cough after pre...

August 2023

This month features many of the big reveals from the ACS fall 2023 first disclosures including Nurix’s BTK degrader and RAPT’s CCR4 autoimmune therapy. Several of the molecules making the August list are in Ph. III clinical trials such as Vertex’s sodium channel inhibitor for acute pain and Denali Therapeutics’ CNS-penetrant eIF2B activator for ALS. We’ll have more detailed case studies on these molecules coming soon, but in the meantime you can check out some recent articles about the following here: VX-548 - oral NaV1.8 selective inhibitor developed by Vertex Pharmaceuticals for acute pain i...

This month features many of the big reveals from the ACS fall 2023 first disclosures including Nurix’s BTK degrader and RAPT’s CCR...

A DCAF1 Ligand Designed for Targeted Protein Degradation

Targeted protein degraders continue to show differentiation from traditional small molecules in terms of both efficacy and safety. To expand the scope of targeted protein degradation (TPD), there has been significant interest throughout the industry in leveraging new E3 ligases beyond CRBN, VHL, MDM2, cIAP, and SCF.

Targeted protein degraders continue to show differentiation from traditional small molecules in terms of both efficacy and safety....

The First Isoform-Selective FGFR2 Inhibitor

The FGFR family of receptors are well-validated targets in cancer, and several pan-FGFR inhibitors that have strong activity against FGFR1-4 have reached approval including pemigatinib, infigratinib, futibatinib, and erdafitinib. While specific FGFRs like FGFR2 can drive cancers like cholangiocarcinoma, broad inhibition of FGFRs leads to significant off-target toxicities, such as hyperphosphatemia from FGFR1 inhibition or diarrhea from FGFR4 inhibition.

The FGFR family of receptors are well-validated targets in cancer, and several pan-FGFR inhibitors that have strong activity again...

A Novel Class of Brain-Penetrant, Covalent Antiparasitic Drugs from Novartis

Recently, Novartis disclosed a new class of brain-penetrant, covalent agents against kinetoplastid parasites in Science. Kinetoplastid parasites cause Chagas disease (T. cruzi), sleeping sickness (T. brucei), and leishmaniasis (Leishmania), but there are few effective treatment options, especially for infections in the brain (e.g. stage II sleeping sickness).

Recently, Novartis disclosed a new class of brain-penetrant, covalent agents against kinetoplastid parasites in Science. Kinetopla...

A CNS-Penetrant KRASG12C Inhibitor Intended for CNS-Metastatic Cancers

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.

AZD4747 is a CNS-penetrant, oral KRAS G12C covalent inhibitor for the treatment of CNS-metastatic KRAS-mutant cancers. KRAS inhibi...

Methods for Identifying Ligand Binding Sites in Drug Discovery

Understanding how a small molecule ligand binds to its target is valuable in drug discovery, because it enables more efficient optimization through structure-based design, better mechanistic understanding of molecular pharmacology, and greater confidence in the therapeutic hypothesis from both safety and efficacy perspectives. Recently, Drug Hunter highlighted methods for target identification when the target is unknown.

Understanding how a small molecule ligand binds to its target is valuable in drug discovery, because it enables more efficient opt...

An oral GLP-1R agonist competing with peptide injectables for diabetes and obesity

Peptidic GLP-1R agonists have received significant media coverage over the past year. Shortages of the semaglutide-based injectable diabetes medication Ozempic, which accounts for 40% of GLP-1R agonist US market share, have even emerged, driven by overwhelming demand for the weight loss formulation Wegovy, both for treatment of obesity and for short-term weight loss popularized by celebrities on social media.

Peptidic GLP-1R agonists have received significant media coverage over the past year. Shortages of the semaglutide-based injectabl...