Revolution Medicines is developing a portfolio of what we believe to be the first potent, selective and cell-active inhibitors of the active, GTP-bound form of RAS, or RAS(ON). We believe that inhibitors of mutant, oncogenic RAS(ON) will be highly effective at suppressing cell growth and survival, as well as less susceptible to adaptive resistance mechanisms described for RAS(OFF) inhibitors.

Initially, we will prioritize four mutant RAS(ON) targets: KRASG12C, KRASG13C, KRASG12D and NRASG12C. These efforts are underpinned by our proprietary tri-complex technology platform, which enables our discovery and development of a broad portfolio of genetically targeted RAS(ON) inhibitors.

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The RAS family of proteins occupies a central and critical position within the broader RAS signaling pathway, playing a key role in the cellular signal transduction cascade.

These RAS proteins, which cycle between the inactive RAS(OFF) form and the active RAS(ON) form, engage and activate downstream molecules that play crucial roles in cell regulation. Mutant forms of RAS that bias the proteins to the RAS(ON) state, and thereby make them significantly more active than normal, can cause cancers such as lung and colon cancer. 

A broad range of oncogenic RAS mutations cause human cancers. These span three different RAS isoforms (KRAS, NRAS and HRAS), with nearly 20 different oncogenic driver mutations present within each isoform. However, despite this far-reaching impact, the development of targeted therapies for RAS-driven cancers has proven extremely challenging. Several of these proteins possess particular structural properties, such as flat surfaces and a lack of typical binding pockets, that make them hard to target pharmacologically.  

We are addressing the challenges of drugging RAS mutants by leveraging our proprietary tri-complex technology platform. This approach is inspired by a biological phenomenon observed in nature, and exemplified by rapamycin or cyclosporine. Our inhibitors drive formation of tri-complexes that exploit the surfaces of two adjacent proteins, a chaperone protein and the target protein, to form a new ligand-binding pocket. The chaperone protein in the tri-complex helps to form the ligand-binding site for the small molecule inhibitor. Further, by physically participating in the tri-complex in the presence of the compound, the chaperone protein sterically occludes the target protein (e.g., RAS(ON)) and prevents interaction with affiliated proteins, such as the RAS effector kinase RAF, required for propagating oncogenic signals.

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Revolution Medicines’ tri-complex drug discovery platform is enabling the targeted inhibition of active RAS(ON).

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Initially, we will prioritize four mutant RAS(ON) targets: KRASG12C, KRASG13C, KRASG12D and NRASG12C. Each of these programs is precisely matched to a specific RAS tumor genotype, allowing for the development of RAS(ON) mutant-selective inhibitors that can be used as targeted monotherapies for specific RAS-driven cancers. 

In addition, these inhibitors can be used in novel treatment combinations with other inhibitors, such as SHP2, to attack multiple targets within the RAS pathway simultaneously to defeat cancer cell addiction and related resistance mechanisms.

 

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