JAB-21822 is a KRAS G12C inhibitor independently developed by Jacobio. From the in-house preclinical head-to-head study, this compound has superior oral bioavailability and systemic drug exposure, better pharmacokinetic profiles and tolerance, and is a potential best-in-class compound.
Preclinical data has shown that JAB-21822 can be used as monotherapy to treat solid tumors with KRAS G12C mutation. Meanwhile, after the development of resistance to KRAS G12C inhibitor treatment, JAB-21822 combined with SHP2 inhibitor can effectively overcome and reverse the resistance to KRAS inhibitors. Jacobio has independently developed both SHP2 inhibitor and KRAS G12C inhibitor, and their combination is the ideal treatment combination for solid tumor patients with KRAS G12C mutation.
At present, Jacobio has initiated phase I/II clinical trials in patients with advanced solid tumors in China and the United States.
KRAS is the oncogene with the highest mutation frequency in human cancer, and KRAS G12C mutation is a common oncogenic mutation in tumors. KRAS G12C mutation leads KRAS to be constitutively activated, which continuously activates downstream signaling pathways such as RAF-MEK-ERK and drives tumor cells to proliferate continuously, leading to carcinogenesis.
For a long time, due to the smooth surface of KRAS protein and the lack of small-molecule binding pocket, effective KRAS inhibitors have not been found. Through its own allosteric inhibitor platform, Jacobio has found a unique binding pocket on the surface of KRAS G12C, and designed a small-molecular allosteric inhibitor JAB-21822, which can potently and selectively inhibit the activity of KRAS G12C through covalent binding, and has favorable anti-tumor effects. JAB-21822 is expected to benefit non-small cell lung cancer and colorectal cancer patients with KRAS G12C mutation, and open up new treatment strategy.
JAB-21822 is a potent and irreversible KRAS G12C inhibitor. JAB-21822 covalently binds to the mutated cysteine residue on the site 12 of GDP-bound KRAS G12C, which locks KRAS G12C in an inactivated state, thus blocking KRAS-dependent signal transduction, inhibiting the growth and proliferation of tumor cells and inducing apoptosis.
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