Oritinib(Synonyms: SH-1028)

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Oritinib (Synonyms: SH-1028)

SH-1028 是一种不可逆的第三代 EGFR TKI，可克服 T790M 介导的非小细胞肺癌耐药。SH-1028 是 EGFR 激酶活性的突变选择性抑制剂，抑制 EGFRWT、EGFRL858R、EGFRL861Q、EGFRL858R/T790M、EGFRd746-750 和 EGFRd746-750/T790M 激酶，IC50 值分别为 18、0.7、4、0.1、1.4 和 0.89 nM。

Oritinib(Synonyms: SH-1028)

Oritinib Chemical Structure

CAS No. : 2035089-28-0

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生物活性

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].

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)

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].

Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.

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).

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].

Shanghai Jinpan Biotech Co Ltd 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 [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 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.

分子量

539.67

Formula

C31H37N7O2
CAS 号

2035089-28-0
运输条件

Room temperature in continental US; may vary elsewhere.
储存方式

Please store the product under the recommended conditions in the Certificate of Analysis.
参考文献

  • [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.

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