Vactosertib is an orally bioavailable TGFβ type I receptor kinase inhibitor, that has demonstrated safety, tolerability, and clinical efficacy in combination with pomalidomide in a Ph. Ib trial for RRMM.

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.

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.

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).

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.