RMC-5127 is a small molecule inhibitor that binds to GTP-targeted KRAS G12V, with oral bioavailability and blood-brain barrier permeability. RMC-5127 inhibits the activities of the RAS and MAPK pathways, suppresses the proliferation of KRAS G12V -mutant cancer cells and induces their apoptosis. RMC-5127 can be used for the research of KRAS G12V -mutant non-small cell lung cancer, pancreatic ductal adenocarcinoma, colorectal cancer and intracranial KRAS G12V tumors [1].
In Vivo, RMC-5127 (3-200 mg/kg; p.o.; once daily; up to 40 days) drives dose-dependent, profound anti-tumor activity in subcutaneous NCI-H441 KRASG12V/WT NSCLC xenografts, with complete or near-complete tumor regression achieved at doses of 100 mg/kg and 200 mg/kg once daily[1]. RMC-5127 (3-200 mg/kg; p.o.; single dose) achieves dose-dependent exposure in blood and NCI-H441 KRASG12V/WT tumors, with MAPK pathway inhibition (measured by DUSP6 mRNA suppression) having an EC50 of 157 nM[1]. RMC-5127 (100 mg/kg; p.o.; once daily; 7 days) achieves measurable brain exposure in naive BALB/c mice, with a brain-to-blood concentration ratio of 0.14 at 4 hours post-last dose[1]. RMC-5127 (100-200 mg/kg; p.o.; once daily; up to 70 days) drives durable anti-tumor activity in intracranial NCI-H441-Luc KRASG12V/WT NSCLC xenografts, with profound tumor regression achieved at a dose of 200 mg/kg once daily[1].
In Vitro, RMC-5127 (10-11 M to 10-6 M) potently disrupts KRASG12V-RAF binding in a cellular NanoBRET assay with a median EC50 of 2.1 nM and 93% median maximum inhibition, demonstrating 26-fold selectivity over K/N/HRAS wildtype[1]. RMC-5127 (10-12 M to 10-6 M) potently inhibits MAPK pathway activity in CAPAN-1 (KRASG12V) cells with an IC50 of 0.6 nM for pERK inhibition[1]. RMC-5127 suppresses RAS pathway activity, inhibits proliferation, and induces apoptosis in a panel of KRASG12V mutant human cancer cells, with a median maximum proliferation inhibition of 93%, while only causing submaximal inhibition in K/N/HRAS wildtype cancer cells[1].
References:
[1]. Zhe Chen, et al. RMC-5127, a first-in-class, orally bioavailable mutant-selective RASG12V(ON) inhibitor is central nervous system (CNS)-penetrant and demonstrates anti-tumor activity in a preclinical intracranial xenograft model. Cancer Res (2024) 84 (6_Supplement): 3340.
In Vivo, RMC-5127 (3-200 mg/kg; p.o.; once daily; up to 40 days) drives dose-dependent, profound anti-tumor activity in subcutaneous NCI-H441 KRASG12V/WT NSCLC xenografts, with complete or near-complete tumor regression achieved at doses of 100 mg/kg and 200 mg/kg once daily[1]. RMC-5127 (3-200 mg/kg; p.o.; single dose) achieves dose-dependent exposure in blood and NCI-H441 KRASG12V/WT tumors, with MAPK pathway inhibition (measured by DUSP6 mRNA suppression) having an EC50 of 157 nM[1]. RMC-5127 (100 mg/kg; p.o.; once daily; 7 days) achieves measurable brain exposure in naive BALB/c mice, with a brain-to-blood concentration ratio of 0.14 at 4 hours post-last dose[1]. RMC-5127 (100-200 mg/kg; p.o.; once daily; up to 70 days) drives durable anti-tumor activity in intracranial NCI-H441-Luc KRASG12V/WT NSCLC xenografts, with profound tumor regression achieved at a dose of 200 mg/kg once daily[1].
In Vitro, RMC-5127 (10-11 M to 10-6 M) potently disrupts KRASG12V-RAF binding in a cellular NanoBRET assay with a median EC50 of 2.1 nM and 93% median maximum inhibition, demonstrating 26-fold selectivity over K/N/HRAS wildtype[1]. RMC-5127 (10-12 M to 10-6 M) potently inhibits MAPK pathway activity in CAPAN-1 (KRASG12V) cells with an IC50 of 0.6 nM for pERK inhibition[1]. RMC-5127 suppresses RAS pathway activity, inhibits proliferation, and induces apoptosis in a panel of KRASG12V mutant human cancer cells, with a median maximum proliferation inhibition of 93%, while only causing submaximal inhibition in K/N/HRAS wildtype cancer cells[1].
References:
[1]. Zhe Chen, et al. RMC-5127, a first-in-class, orally bioavailable mutant-selective RASG12V(ON) inhibitor is central nervous system (CNS)-penetrant and demonstrates anti-tumor activity in a preclinical intracranial xenograft model. Cancer Res (2024) 84 (6_Supplement): 3340.