BI-3406

KRAS remains an elusive target in cancer. Directly targeting KRAS proteins is particularly difficult due to the intrinsic molecular characteristics of KRAS proteins, i.e., the lack of small-molecule binding sites and exceptionally high affinity for GTP/GDP. In this context, down-regulation of KRAS activity by targeting SOS1, instead, to block the formation of the SOS1‒KRAS complex has been investigated as a potential valuable therapeutic strategy. To date (November 2023), there are three SOS1 small-molecule binders (the Bayer compound BAY-293, the Boehringer Ingelheim compound BI-3406, and the Mirati Therapeutics molecule MRTX0902) that have been identified as potent and selective inhibitors of the SOS1‒KRAS protein-protein interaction, and whose chemical structures are available. All three compounds possess SOS1 binding activity in the nanomolar range, X-ray co-crystal structures of each compound bound to SOS1 are available, and they all have orally bioavailable properties. Although the quinazoline-based BI-3406 compound is not a clinical candidate, it is a powerful chemical probe to interrogate the effect of the SOS1‒KRAS complex disruption in a broad range of KRAS-driven cancers (such as pancreatic, lung and colorectal cancers), in both cell-based assays and in in vivo mouse models.

This probe has been studied with a rather rigorous series of control experiments, including single point mutations that block binding to SOS1. This probe has also been explored in a kinase panel and for binding to the nearest off-target, SOS2. A strong set of biochemical, structural and cellular studies support on-target activity in cells and mice.

BI-3406 has been extensively characterized to bind to the catalytic domain of SOS1 (as demonstrated by numerous biophysical, including X-ray crystallography, biochemical, and cellular assays), thereby preventing the interaction with KRAS. PK data guided preliminary in vivo efficacy in mice xenografts and PDX models of PCa with the probe delivered orally as a single agent or combined with a MEK inhibitor, and it resulted very effective in suppressing the growth of KRAS-driven tumors.