“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 [...]

Last year, Biogen announced that it would acquire Texas biotech Reata Pharmaceuticals for $7.3B. Reata’s lead molecule, omaveloxolone (SKYCLARYS®), an oral, reversible covalent inhibitor of the E3 ligase KEAP1, became the first drug approved for Friedrich’s Ataxia. Omaveloxolone was previously highlighted as a Molecule of the Month in July 2023. Now, this 2023 Molecule of the Year nominee reflects a historic milestone for neurological drug discovery. This comprehensive explainer dives into Nrf2 target rationale, how it works, how the drug was discovered, its synthesis, and why it’s a big deal.

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.

BridgeBio’s BBO-8520 is a selective, covalent KRAS(G12C) inhibitor which differentiates itself from the pack by engaging the (ON) state of the protein, potentially conferring increased clinical benefit in KRAS(G12C)-driven cancers, including overcoming resistance to current treatments. Disclosed at the 2024 AACR Annual Meeting in San Diego, is currently in a Ph. I trial in patients with advanced non-small-cell lung cancer. This article covers the structure, mechanism of action and preclinical efficacy that marks this compound out as one to watch.

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.