KRAS is the most frequently mutated oncogene with high prevalence in pancreatic, colorectal, and non-small cell lung tumors. KRAS signaling is tightly regulated and various factors, including negative feedback pathways have limited the clinical efficacy of inhibitors of downstream MAPK signaling in the KRAS mutant context. Here we report the discovery of BI-3406 and demonstrate it is a highly potent and selective, orally bioavailable SOS1::KRAS inhibitor which binds to the catalytic domain of the guanine nucleotide exchange factor (GEF) SOS1 thereby preventing the interaction with KRAS-GDP. BI-3406 does not block the interaction of KRAS with SOS2 but elicits activity on a broad panel of KRAS oncogenic variants, including all major G12 and G13 oncoproteins. In KRAS-dependent cancers, BI-3406 potently reduces the formation of GTP-loaded KRAS, and inhibits MAPK pathway signaling. Down-modulation of this signaling cascade by BI-3406 in KRAS G12 or G13 mutant cells effectively limits cell proliferation. As a monotherapy, BI-3406 modulates signaling, as assessed by p-ERK and target genes, and displays marked anti-tumor efficacy in KRAS mutant xenografts. Due to BI-3406 blocking the negative feedback relief induced by MAPK inhibition, it has the potential to sensitize KRAS-dependent cancers to MEK inhibitor treatment. Combination with MEK inhibition leads to profound pathway blockade and tumor regressions in vivo. The combination of SOS1 and MEK inhibition is a potential therapy for the majority of KRAS-driven cancers including those fuelled by the most prevalent KRAS mutant oncoproteins. Furthermore, the pharmacological properties of BI-3406 and close analogues hold the promise of a significant treatment benefit in a broad patient population that is currently lacking precision medicine options. A Phase 1 clinical trial is in preparation for patients with advanced KRAS-mutated cancers to evaluate safety, tolerability, pharmacokinetic and pharmacodynamic properties, and preliminary efficacy of BI 1701963, a SOS1::KRAS inhibitor closely related to BI-3406.

Citation Format: Marco H Hofmann, Michael Gmachl, Jürgen Ramharter, Fabio Savarese, Daniel Gerlach, Joseph R Marszalek, Michael P Sanderson, Francesca Trapani, Dirk Kessler, Klaus Rumpel, Dana-Adriana Botesteanu, Peter Ettmayer, Heribert Arnhof, Thomas Gerstberger, Christiane Kofink, Tobias Wunberg, Szu-Chin Fu, Jessica Teh, Christopher P. Vellano, Jonathan C. O’Connell, Rachel L Mendes, Juergen Moll, Timothy P. Heffernan, Mark Pearson, Darryl B McConnell, Norbert Kraut. Discovery of BI-3406: A potent and selective SOS1::KRAS inhibitor opens a new approach for treating KRAS-driven tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PL06-01. doi:10.1158/1535-7163.TARG-19-PL06-01