MRTX0902 is a potent SOS1 inhibitor which can be used for the therapeutic intervention of KRAS-driven (Kirsten rat sarcoma virus driven) cancers. The structure of MRTX0902 is showed in figure 1.
SOS1 is a guanine nucleotide exchange factor (GEF) which interacts with RAS proteins to phosphorylate GDP (guanosine diphosphate) into GTP (guanosine triohosphte), or from an inactive state to an active state to signal cell proliferation.
Ras proteins (H-Ras, K-Ras4A and 4B, and N-Ras) are regulators of signal transduction, mutated in 30 percent of human cancers, and targets for novel approaches for cancer treatment.
Rat sarcoma (RAS) is the most frequently mutated oncogene in human cancer, with KRAS being the most commonly mutated RAS isoform. Overall, KRAS accounts for 85% of RAS mutations observed in human cancers and is present in 35% of lung adenocarcinomas (LUADs).
KRAS functions as a GDP/GTP binary switch, which controls important signal transduction from activated membrane receptors to intracellular molecules. KRAS mutations at positions 12, 13, 61, and 146 lead to a shift toward the active KRAS form through impairing nucleotide hydrolysis and/or activating nucleotide exchange. Key effector pathways downstream of oncogenic KRAS include mitogenactivated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K), and Ras-like (Ral) GEF (RalGEF); all of these effectors are responsible for cell proliferation, cell cycleregulation, metabolic changes, cell survival, and cell differentiation that results in tumor induction or growth. Oncogenic KRAS also induces secretion of molecules that affect surrounding components of the stroma, such as fibroblasts, innate and adaptive immune cells, in a paracrine manner. These stroma cells in turn promote cancer malignancy (see figure 2).
SOSs (existing as two homologs, SOS1 and SOS2) are the most universal and widely expressed RAS-GEF activators in mammalian cells. Oncogenic KRAS mutations cause aberrant regulation of the KRAS cycle, leading to human pathologies including hereditary developmental syndromes and a wide variety of sporadic 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. SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers.
A potential approach to KRAS inhibition involves targeting proteins that regulate KRAS. In particular, the guanine nucleotide exchange factor SOS1 has emerged as a viable target for the treatment of KRAS-driven cancers. By preventing the SOS1-mediated loading of GTP onto KRAS, KRAS can be maintained in an inactive state. Through this mechanism, the overactivation of downstream signaling pathways and the corresponding unchecked cellular proliferation that is characteristic of KRAS-driven cancers may be suppressed.
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