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

Autor:	Hofmann MH; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. marco.hofmann@boehringer-ingelheim.com norbert.kraut@boehringer-ingelheim.com., Gmachl M; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Ramharter J; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Savarese F; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Gerlach D; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Marszalek JR; TRACTION Platform, Division of Therapeutics Discovery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Sanderson MP; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Kessler D; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Trapani F; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Arnhof H; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Rumpel K; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Botesteanu DA; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Ettmayer P; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Gerstberger T; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Kofink C; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Wunberg T; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Zoephel A; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Fu SC; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Teh JL; TRACTION Platform, Division of Therapeutics Discovery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Böttcher J; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Pototschnig N; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Schachinger F; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Schipany K; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Lieb S; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Vellano CP; TRACTION Platform, Division of Therapeutics Discovery, The University of Texas MD Anderson Cancer Center, Houston, Texas., O'Connell JC; Forma Therapeutics, Watertown, Massachusetts., Mendes RL; Forma Therapeutics, Watertown, Massachusetts., Moll J; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Petronczki M; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Heffernan TP; TRACTION Platform, Division of Therapeutics Discovery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Pearson M; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., McConnell DB; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Kraut N; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. marco.hofmann@boehringer-ingelheim.com norbert.kraut@boehringer-ingelheim.com.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2021 Jan; Vol. 11 (1), pp. 142-157. Date of Electronic Publication: 2020 Aug 19.
DOI:	10.1158/2159-8290.CD-20-0142
Abstrakt:	KRAS 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. See related commentary by Zhao et al., p. 17 . This article is highlighted in the In This Issue feature, p. 1 . (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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