生物活性 | Oritinib (SH-1028), an irreversible third-generationEGFRTKI, overcomes T790M-mediated resistance in non-small cell lungcancer. Oritinib (SH-1028), a mutant-selective inhibitor ofEGFRkinase activity, inhibitsEGFRWT,EGFRL858R,EGFRL861Q,EGFRL858R/T790M,EGFRd746-750andEGFRd746-750/T790Mkinases, withIC50s of 18, 0.7, 4, 0.1, 1.4 and 0.89 nM, respectively[1]. |
IC50& Target[1] | EGFR (WT) 18 nM (IC50) | EGFRL858R 0.7 nM (IC50) | EGFRL861Q 4 nM (IC50) | EGFRL858R/T790M 0.1 nM (IC50) | EGFRd746-750 1.4 nM (IC50) | EGFRd746-750/T790M 0.89 nM (IC50) |
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体外研究 (In Vitro) | 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].
Cell Proliferation Assay[1] Cell Line: | A431 (EGFRWT), H3255 (EGFRL858R), PC-9 (EGFRd746-750) and NCI-H1975 (EGFRL858R/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 IC50s 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 (IC50=778.89±134.74 nM). |
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体内研究 (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[1]. Oritinib shows good bioavailability, and is distributed extensively from the plasma to the tissues[1].
Animal Model: | 6-8 weeks old female mice bearing NCI-H1975 and A431 xenograft models[1] | 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[1] | Dosage: | 2.5, 5, and 15 mg/kg (Pharmacokinetic Analysis) | Administration: | Oral administration for 1 day or 14 consecutive days. | Result: | The Tmaxis 1.5-2 h, indicating rapidly distributed into tissues, including lung tumor tissues. The AUC0–tvalues 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. |
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运输条件 | Room temperature in continental US; may vary elsewhere. |
储存方式 | Powder | -20°C | 3 years | | 4°C | 2 years | In solvent | -80°C | 6 months | | -20°C | 1 month |
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溶解性数据 | In Vitro: DMSO : 125 mg/mL(231.62 mM;Need ultrasonic) 配制储备液 1 mM | 1.8530 mL | 9.2649 mL | 18.5298 mL | 5 mM | 0.3706 mL | 1.8530 mL | 3.7060 mL | 10 mM | 0.1853 mL | 0.9265 mL | 1.8530 mL |
*请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效。 储备液的保存方式和期限:-80℃, 6 months; -20℃, 1 month。-80℃ 储存时,请在 6 个月内使用,-20℃ 储存时,请在 1 个月内使用。 |