2-Propenamide, N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)-2-pyrimidinyl]amino]phenyl]-

Biological Activity

Oritinib (SH-1028), an irreversible third-generation EGFR TKI, overcomes T790M-mediated resistance in non-small cell lung cancer. Oritinib (SH-1028), a mutant-selective inhibitor of EGFR kinase activity, inhibits EGFRWT, EGFRL858R, EGFRL861Q, EGFRL858R/T790M, EGFRd746-750 and EGFRd746-750/T790M kinases, with IC50s of 18, 0.7, 4, 0.1, 1.4 and 0.89 nM, respectively[1]. Oritinib (SH-1028) binds irreversibly to EGFR kinase by targeting cysteine-797 residue in the ATP binding site via covalent bond formation[1].Oritinib (0.001-10 μM) potently and selectively targets mutant EGFR cell lines in vitro[1].Oritinib (0.1 μM) continuously inhibits the phosphorylation of EGFR in PC-9 and NCI-H1975 cells at lower concentrations or even drug-free for at least 6 h[1]. Oral administration of Oritinib at a daily dose of 5 mg/kg significantly inhibits proliferation of tumor cells with EGFR sensitive mutation (exon 19 del) and resistant mutation (T790 M) for consecutive 14 days, with no TKI-induced weight loss in mouse xenograft models[1]. Oritinib shows good bioavailability, and is distributed extensively from the plasma to the tissues[1].

References

[1]. Luwei Han, et al. SH-1028, An Irreversible Third-Generation EGFR TKI, Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer. Front Pharmacol. 2021 Apr 27;12:665253.