CH7057288 shows selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppresses proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. CH7057288 suppresses mitogen-activated protein kinase (MAPK) and E2F pathways as downstream signaling of TRK fusion.
In vivo
Strong in vivo tumor growth inhibition is observed in subcutaneously implanted xenograft tumor models of TRK fusion-positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induces tumor regression and improves event-free survival. CH7057288 induces potent tumor growth inhibition against all three models, with remarkable tumor regression in CUTO-3 and MO-91. CH7057288 exhibits dose-dependent exposure. Because of relatively short terminal half-life (3 to 5 hours), the plasma concentration 24 hours after dose dropped to approximately a few tenths to a hundredth of Tmax.
Cell Research(from reference)
Cell lines：The NSCLC cell line CUTO-3, CRC cell line KM12-Luc, and acute myeloid leukemia cell line MO-91 harbor MPRIP-NTRK1, TPM3-NTRK1, and ETV6-NTRK3, respectively
1.Ito T, Kinoshita K, Tomizawa M, Shinohara S, Nishii H, Matsushita M, Hattori K, Kohchi Y, Kohchi M, Hayase T et al.. (2022) Discovery of CH7057288 as an Orally Bioavailable, Selective, and Potent pan-TRK Inhibitor.. J Med Chem, 65 (18):(12427-12444). [PMID:36066182]
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J2213386