SOS1 inhibitor MRTX0902

An orally available, brain-penetrant, phthalazine-based inhibitor of the guanine nucleotide exchange factor (GEF) Son of sevenless homolog 1 (SOS1), with potential antineoplastic activity. Upon oral administration, SOS1 inhibitor MRTX0902 selectively targets and binds to SOS1, thereby preventing the interaction of SOS1 with Kirsten rat sarcoma viral oncogene homolog (KRAS) in the guanosine diphosphate (GDP)-bound 'off' state, which is the inactivated state of KRAS. This abrogates the exchange of RAS-bound GDP for guanosine triphosphate (GTP) and prevents the formation of GTP-loaded KRAS, which is the activated 'on' state of KRAS. This prevents activation of downstream RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway by GTP-loaded KRAS. This inhibits mutant KRAS-dependent signaling and may inhibit growth and survival of KRAS-expressing tumor cells. KRAS is a member of the RAS family of oncogenes that is mutated in many cancer cell types. Mutations of KRAS may induce constitutive signal transduction leading to tumor cell proliferation, survival, invasion, and metastasis. SOS1 regulates the KRAS GDP-GTP cycle and promotes nucleotide exchange and formation of 'active' KRAS-GTP.