Details

Autor(en) / Beteiligte

• Hofmann, Marco H
• Gmachl, Michael
• Ramharter, Juergen
• Savarese, Fabio
• Gerlach, Daniel
• Marszalek, Joseph R
• Sanderson, Michael P
• Kessler, Dirk
• Trapani, Francesca
• Arnhof, Heribert
• Rumpel, Klaus
• Botesteanu, Dana-Adriana
• Ettmayer, Peter
• Gerstberger, Thomas
• Kofink, Christiane
• Wunberg, Tobias
• Zoephel, Andreas
• Fu, Szu-Chin
• Teh, Jessica L
• Böttcher, Jark
• Pototschnig, Nikolai
• Schachinger, Franziska
• Schipany, Katharina
• Lieb, Simone
• Vellano, Christopher P
• O'Connell, Jonathan C
• Mendes, Rachel L
• Moll, Jurgen
• Petronczki, Mark
• Heffernan, Timothy P
• Pearson, Mark
• McConnell, Darryl B
• Kraut, Norbert

Titel

BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition

Ist Teil von

• Cancer discovery, 2021-01, Vol.11 (1), p.142-157

Ort / Verlag

United States

Erscheinungsjahr

2021

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• is the most frequently mutated driver of pancreatic, colorectal, and non-small cell lung cancers. Direct KRAS blockade has proved challenging, and inhibition of a key downstream effector pathway, the RAF-MEK-ERK cascade, has shown limited success because of activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective, and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1, thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors. SIGNIFICANCE: To date, there are no effective targeted pan-KRAS therapies. In-depth characterization of BI-3406 activity and identification of MEK inhibitors as effective combination partners provide an attractive therapeutic concept for the majority of KRAS-mutant cancers, including those fueled by the most prevalent mutant KRAS oncoproteins, G12D, G12V, G12C, and G13D. . .