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Oritinib (SH-1028) mesylate is a selective, orally active, and pyrimidine-based irreversible inhibitor of EGFR with an IC50 of 18 nM. Oritinib (SH-1028) mesylate exhibits potent activity against EGFR sensitive and resistant (T790 M) mutations. Oritinib (SH-1028) mesylate significantly inhibits proliferation of tumor cells with EGFR sensitive and resistant mutation[1]. | [in vivo]
Oritinib (SH-1028) (p.o.; once daily for consecutive 14 days; 2.5-15 mg/kg) mesylate inhibits EGFR-mutant tumor progression but not wild-type EGFR in vivo[1].
Oritinib (SH-1028) (p.o.; once daily for consecutive 14 days; 2.5-15 mg/kg) mesylate only induces a moderate tumor growth inhibition in A431 (wild-type EGFR) tumor xenografts, while causes profound and sustained tumor shrinkage in both NCI-H1975 and PC-9 xenograft models with EGFR mutations with 5 mg/kg/day[1].
Oritinib (SH-1028) (p.o.; once daily for consecutive 14 days; 2.5-15 mg/kg) mesylate shows good bioavailability, and is distributed extensively from the plasma to the tissues with Tmax of 1.5-2 h, and AUC0–t values of SH-1028 in plasma are 118, 300 and 931 ng × h/ml on Day 1, while 272, 308 and 993 ng × h/ml on Day 14[1]. | Animal Model: | Nu/Nu female nude mice (6-8 weeks) bearing human lung cancer cell lines[1] | | Dosage: | 2.5, 5, and 15 mg/kg (SH-1028) and control group (osimertinib, 5 mg/kg) | | Administration: | p.o.; once daily for consecutive 14 days | | Result: | Only induced a moderate tumor growth inhibition in A431 (wild-type EGFR) tumor xenografts, while caused profound and sustained tumor shrinkage in both NCI-H1975 and PC-9 xenograft models with EGFR mutations with 5 mg/kg/day.
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| [IC 50]
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) | [References]
[1] Han L, et al. SH-1028, An Irreversible Third-Generation EGFR TKI, Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer. Front Pharmacol. 2021;12:665253. DOI:10.3389/fphar.2021.665253 |
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