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Review
. 2021 Jun:62:109-118.
doi: 10.1016/j.cbpa.2021.02.014. Epub 2021 Apr 10.

Targeting Son of Sevenless 1: The pacemaker of KRAS

Dirk Kessler  1 , Daniel Gerlach  1 , Norbert Kraut  1 , Darryl B McConnell  2
Affiliations
Free article
Review

Targeting Son of Sevenless 1: The pacemaker of KRAS

Dirk Kessler et al. Curr Opin Chem Biol. 2021 Jun.
Free article

Abstract

Son of Sevenless (SOS) is a guanine nucleotide exchange factor that activates the important cell signaling switch KRAS. SOS acts as a pacemaker for KRAS, the beating heart of cancer, by catalyzing the "beating" from the KRAS(off) to the KRAS(on) conformation. Activating mutations in SOS1 are common in Noonan syndrome and oncogenic alterations in KRAS drive 1 in seven human cancers. Promising clinical efficacy has been observed for selective KRASG12C inhibitors, but the vast majority of oncogenic KRAS alterations remain undrugged. The discovery of a druggable pocket on SOS1 has led to potent SOS1 inhibitors such as BI-3406. SOS1 inhibition leads to antiproliferative effects against all major KRAS mutants. The first SOS1 inhibitor has entered clinical trials for KRAS-mutated cancers. In this review, we provide an overview of SOS1 function, its association with cancer and RASopathies, known SOS1 activators and inhibitors, and a future perspective is provided.

Keywords: Cancer; KRAS; Medicinal chemistry; Protein–protein interaction; RASopathies; SOS1.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are currently employees of Boehringer Ingelheim.

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