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...

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.

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?

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.

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...

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.

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!

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.

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.

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

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.

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...

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.

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).

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.

Thyroid hormone receptor β (TRβ, THRβ or THR-β) agonists have seen a surge of interest in non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), largely thanks to impressive Ph. III clinical data from resmetirom, a Breakthrough Therapy and 2022 Molecule of the Year candidate developed by Madrigal and originated at Roche. If its recently accepted NDA is approved, resmetirom could become the first drug to achieve accelerated approval for NASH after decades of research effort.

Obtaining adequate drug exposure in the brain is key to treating CNS diseases effectively. Recently, Dennis Koester gave us a crash course in CNS drug discovery in a Drug Hunter Flash Talk. Here, he sums up some key points on how to find compounds that cross the blood-brain barrier.

The arachidonic acid (AA) metabolite, 20-hydroxy-5,8,11,14-eicosatetranoic acid (20-HETE), has been extensively studied as a modulator of kidney function and a mediator of kidney diseases over decades. The receptor for 20-HETE, the G-coupled protein receptor GPR75, was only recently identified (2017), and GPR75/20-HETE pathway modulators are of industry interest in many disease areas including obesity (e.g. 2020 Regeneron patent filing) and kidney diseases (e.g. 2018 Taisho patent filing).