Oritinib

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 EGFR WT , EGFR L858R , EGFR L861Q , EGFR L858R/T790M , EGFR d746-750 and EGFR d746-750/T790M kinases, with IC 50 s of 18, 0.7, 4, 0.1, 1.4 and 0.89 nM, respectively In Vitro Oritinib (SH-1028) binds irreversibly to EGFR kinase by targeting cysteine-797 residue in the ATP binding site via covalent bond formation. Oritinib (0.001-10 μM) potently and selectively targets mutant EGFR cell lines in vitro. 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. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Proliferation AssayCell Line: A431 (EGFR WT ), H3255 (EGFR L858R ), PC-9 (EGFR d746-750 ) and NCI-H1975 (EGFR L858R/T790M ) cells Concentration: 0.001, 0.01, 0.1, 1, and 10 μM Incubation Time: 72 hours Result: Selectively inhibited EGFR-mutated NCI-H1975, H3255 and PC-9 cells, with IC 50 s of 3.93±1.12, 9.39±0.88 and 7.63±0.18 nmol/L, respectively, which were about 198-, 83- and 102-fold more sensitive than the inhibition of wild-type EGFR in A431 cells (IC 50 =778.89±134.74 nM). In Vivo 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 . Oritinib shows good bioavailability, and is distributed extensively from the plasma to the tissues . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: 6-8 weeks old female mice bearing NCI-H1975 and A431 xenograft models Dosage: 2.5, 5, and 15 mg/kg Administration: Orally administrated once daily for consecutive 14 days Result: Led to a significant inhibition of tumor cell growth in both PC-9 (exon 19 del) and NCI-H1975 (L858R/T790M) xenograft models. Animal Model: NCI-H1975 tumor-bearing mice Dosage: 2.5, 5, and 15 mg/kg (Pharmacokinetic Analysis) Administration: Oral administration for 1 day or 14 consecutive days. Result: The T max is 1.5-2 h, indicating rapidly distributed into tissues, including lung tumor tissues. The AUC 0–t values in plasma were 118, 300 and 931 ng×h/mL on Day 1, while 272, 308 and 993 ng×h/ml on Day 14, respectively. Form:Solid IC50& Target:EGFR (WT) 18 nM (IC 50 ) EGFR L858R 0.7 nM (IC 50 ) EGFR L861Q 4 nM (IC 50 ) EGFR L858R/T790M 0.1 nM (IC 50 ) EGFR d746-750 1.4 nM (IC 50 ) EGFR d746-750/T790M 0.89 nM (IC 50 )

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