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.

Jecure’s JT001 is a selective inhibitor of NLRP3 inflammasome and among the earlier compounds in this now highly competitive space. In 2018, Genentech bought Jecure Therapeutics for an undisclosed amount, gaining access to Jecure’s NLRP3 inhibitor JT001. While there are many other NLRP3 inhibitors now in the space, JT001 is an interesting example of an initial attempt to overcome liver toxicity with well-known NLRP3 inhibitor MCC950. However, the molecule ran into its own kidney toxicity issues, making this an intriguing toxicology case study.

PLX-4545 is an oral CRBN-based molecular glue degrader of IKZF2 in Ph. I trials. It potentially addresses anti-tumor immunity suppression within the TME, critical in checkpoint blocker resistance. Tumors use IKZF2 to regulate the function of regulatory T cells and inhibit effector T cells. IKZF2 depletion in regulatory T cells enhances the anti-tumor response. The discovery and structural data of PLX-4545 were presented by Kevin Freeman-Cook at the ACS Fall 2024 First-Time Disclosures session in Denver, CO. We are reporting the discovery story and its potential impact on immuno-oncology.

Pfizer disclosed the structure and discovery of their oral small molecule BDK inhibitor/degrader, PF-07328948, during the ACS Fall 2024 First-Time Disclosures session in Denver. The team identified a thiophene carboxylic acid-based hit targeting an allosteric pocket on BDK. Through optimization, they overcame challenges such as potential IADRs and BDK-E2 complex stabilization. By manipulating the dihedral angle of the methoxy group, they enhanced binding interactions, verifying PF-07328948's unexpected mechanism of action in vivo. PF-07328948 is currently Ph. I trials.

Arcus Biosciences recently disclosed the structure and discovery story of their oral HIF-2α inhibitor casdatifan (AB521) at the ACS Fall 2024 First Time Disclosures session in Denver. Read on to find out how the team overcame serum shifts and metabolism issues to deliver into the clinic what could potentially be a best-in-class compound, superior to the recently approved inhibitor, belzutifan.