Oritinib

Research use only, not for human use.

Oritinib is an inhibitor of EGFR with IC50s of 18, 0.7, 4, 0.1, 1.4 and 0.89 nM for EGFR (wt), EGFR (L858R), EGFR (L861Q), EGFR (L858R/T790M), EGFR (d746-750), EGFR (d746-750/T790M), respectively. Oritinib can be used in studies about the treatment of non-small cell lung cancer.

Oritinib is an inhibitor of EGFR with IC50s of 18, 0.7, 4, 0.1, 1.4 and 0.89 nM for EGFR (wt), EGFR (L858R), EGFR (L861Q), EGFR (L858R/T790M), EGFR (d746-750), EGFR (d746-750/T790M), respectively. Oritinib can be used in studies about the treatment of non-small cell lung cancer.(In Vitro):Oritinib (0.001, 0.01, 0.1, 1, and 10 μM) selectively inhibits EGFR-mutated NCI-H1975, H3255 and PC-9 cells, with IC50s of 3.932, 9.39 and 7.63 nM, respectively. Oritinib (0.1 μM) continuously inhibits the phosphorylation of EGFR in PC-9 and NCI-H1975 cells.(In Vivo):In female mice bearing NCI-H1975 and A431 xenograft models， Oritinib (2.5, 5, and 15 mg/kg; oral) significantly inhibits proliferation of tumor cells with no TKI-induced weight loss. In NCI-H1975 tumor-bearing mice, Oritinib (2.5, 5, and 15 mg/kg; oral) shows good bioavailability(Tmax = 1.5-2 h) and extensive distribution from the plasma to the tissues. The AUC0–t values in plasma are 118, 300 and 931 ng×h/mL on Day 1, while 272, 308 and 993 ng×h/ml on Day 14, respectively.

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. Cell Proliferation Assay 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).

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. 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 daysResult: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 Tmax is 1.5-2 h, indicating rapidly distributed into tissues, including lung tumor tissues. The AUC0–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.

SH-1028

Angiogenesis

EGFR

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2035089-28-0

539.67

C31H37N7O2

>98% (HPLC)

In Vitro:?DMSO : 125 mg/mL (231.62 mM)

O=C(C=C)NC1=CC(NC=2N=CC=C(N2)C=3C=4C=CC=CC4N5C3CCCC5)=C(OC)C=C1N(C)CCN(C)C

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(-20℃)

With Ice Pack

≥ 2 years