AZD4625 is an orally active, selective irreversible, covalent allosteric GTPase KRAS G12C inhibitor with an IC50 of 3 nM. AZD4625 can inhibit the MAPK pathway (with decreased pCRAF, pMEK, and pERK ) and the PI3K pathway (with decreased pAKT and pS6), and induce cell apoptosis. AZD4625 has no binding and inhibition of wild-type RAS or isoforms carrying non-KRAS G12C mutations. AZD4625 can be used for the study of KRAS G12C mutant non-small cell lung cancer [1] [2].
In Vivo, AZD4625 (Compound 21) (4-100 mg/kg, p.o., once daily for 15-20 days) inhibits tumor growth in KRASG12C MIAPaCa-2 xenograft mice model[1]. AZD4625 (4-100 mg/kg, p.o., once daily for 20-25 days) continuously inhibits tumor regression in the HCI-H358 xenograft mouse model, and appears relatively resistant in the HCI-H358 model, however, when combined with Afatinib and SHP099 shows a powerful anti-tumor effect NCI-H358 and LU99 lung xenograft models[2]. AZD4625 (100 mg/kg, p.o., once daily for 7 days) significantly reduces the lung tumor burden in six KRASG12C patient-derived xenograft (PDX) mice models[2]. AZD4625 (100 mg/kg, p.o., once daily for 21 days) drives changes to the tumor immune microenvironment and that deeper and more durable responses may be achieved if combined with immune checkpoint inhibitors (ICIs) in KRASG12C syngeneic mouse model[2].
In Vitro, AZD4625 (Compound 21) inhibits p90RSK phosphorylation (IC50 = 36 nM) in KRASG12C mutant cells (NCI-H358)[1]. AZD4625 (0.01-3 μM, 0-120 h) reduces proliferation and survival of NCI-H358 cells (IC50 = 4.1 nM) driving cell-cycle arrest and apoptosis[1][2]. AZD4625 enhances the depth and duration of response when combined with the receptor tyrosine kinases (RTK) inhibitor SHP099, the EGFR inhibitor Gefitinib and ErbB inhibitor afatinib in NCI-H358 and NCI-H1373 cells[2].
References:
[1]. Kettle JG, et al. Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C. J Med Chem. 2022 May 12;65(9):6940-6952.
[2]. Chakraborty A, et al. AZD4625 is a Potent and Selective Inhibitor of KRASG12C. Mol Cancer Ther. 2022 Oct 7;21(10):1535-1546.
In Vivo, AZD4625 (Compound 21) (4-100 mg/kg, p.o., once daily for 15-20 days) inhibits tumor growth in KRASG12C MIAPaCa-2 xenograft mice model[1]. AZD4625 (4-100 mg/kg, p.o., once daily for 20-25 days) continuously inhibits tumor regression in the HCI-H358 xenograft mouse model, and appears relatively resistant in the HCI-H358 model, however, when combined with Afatinib and SHP099 shows a powerful anti-tumor effect NCI-H358 and LU99 lung xenograft models[2]. AZD4625 (100 mg/kg, p.o., once daily for 7 days) significantly reduces the lung tumor burden in six KRASG12C patient-derived xenograft (PDX) mice models[2]. AZD4625 (100 mg/kg, p.o., once daily for 21 days) drives changes to the tumor immune microenvironment and that deeper and more durable responses may be achieved if combined with immune checkpoint inhibitors (ICIs) in KRASG12C syngeneic mouse model[2].
In Vitro, AZD4625 (Compound 21) inhibits p90RSK phosphorylation (IC50 = 36 nM) in KRASG12C mutant cells (NCI-H358)[1]. AZD4625 (0.01-3 μM, 0-120 h) reduces proliferation and survival of NCI-H358 cells (IC50 = 4.1 nM) driving cell-cycle arrest and apoptosis[1][2]. AZD4625 enhances the depth and duration of response when combined with the receptor tyrosine kinases (RTK) inhibitor SHP099, the EGFR inhibitor Gefitinib and ErbB inhibitor afatinib in NCI-H358 and NCI-H1373 cells[2].
References:
[1]. Kettle JG, et al. Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C. J Med Chem. 2022 May 12;65(9):6940-6952.
[2]. Chakraborty A, et al. AZD4625 is a Potent and Selective Inhibitor of KRASG12C. Mol Cancer Ther. 2022 Oct 7;21(10):1535-1546.