The guanine nucleotide exchange factor (GEF) protein SOS1 activates RAS by promoting its conversion from the GDP-bound RAS(OFF) state to the GTP-bound RAS(ON) state. SOS1 catalyzes or accelerates this nucleotide exchange reaction in response to upstream signals conveyed by a range of growth factor receptors. It acts by promoting the release of tightly bound GDP and thereby facilitating the binding of GTP to generate RAS(ON). SOS1 itself is activated by RAS through the binding of RAS(ON) to an allosteric site on the SOS1 protein, which leads to a positive feedback loop between SOS1 and RAS that increases the amplitude and duration of RAS signaling. As a result, there is considerable potential for amplification of RAS signals by SOS1. For this reason, SOS1 represents an attractive therapeutic target in RAS driven cancer and we believe SOS1 inhibition represents an attractive companion for combination with RAS-directed inhibitors with potential for unique utility in select RAS-addicted tumor types. Here we describe the development and preclinical profile of a potent, selective, and orally bioavailable in vivo tool compound, RMC-0331, which disrupts the critical interaction between KRAS and SOS1. Using structure-based drug design and building on published structural information, we have produced a differentiated lead series based on a hemi-saturated core with increased potential for drug-like properties. We designed a modular synthetic approach that allowed for the rapid generation of a large number of potential SOS1 inhibitors. This modular approach enabled rapid SAR exploration to optimize potency, physicochemical properties, and in vitro ADME properties. These efforts have resulted in the development of the potent, selective, and orally bioavailable in vivo tool compound RMC-0331. Oral administration of RMC-0331 as a single agent and in combination with other RAS pathway inhibitors demonstrated anti-tumor activity in select RAS-addicted cancer models.

Discovery of a potent, selective, and orally bioavailable SOS1 inhibitor, RMC-0331, an in vivo tool compound that blocks RAS activation via disruption of the RAS-SOS1 interaction

ACS Fall 2021

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