Oritinib

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Oritinib

本产品不向个人销售，仅用作科学研究，不用于任何人体实验及非科研性质的动物实验。

CAS NO:

2035089-28-0

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EGFR^WT、EGFR^L858R、EGFR^L861Q、EGFR^L858R/T790M、EGFR^d746-750和EGFR^{d746-750/T790M}激酶，IC₅₀值分别为 18、0.7、4、0.1、1.4 和 0.89 nM。

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, inhibitsEGFR^WT,EGFR^L858R,EGFR^L861Q,EGFR^L858R/T790M,EGFR^d746-750andEGFR^{d746-750/T790M}kinases, withIC₅₀s of 18, 0.7, 4, 0.1, 1.4 and 0.89 nM, respectively^[1].

IC₅₀& Target^[1]

EGFR (WT)

18 nM (IC₅₀)

EGFR^L858R

0.7 nM (IC₅₀)

EGFR^L861Q

4 nM (IC₅₀)

EGFR^L858R/T790M

0.1 nM (IC₅₀)

EGFR^d746-750

1.4 nM (IC₅₀)

EGFR^{d746-750/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].

Cell Proliferation Assay^[1]

Cell 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 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].

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 T_maxis 1.5-2 h, indicating rapidly distributed into tissues, including lung tumor tissues. The AUC_0–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.

Clinical Trial

分子量

539.67

性状

Solid

Formula

C₃₁H₃₇N₇O₂

CAS 号

2035089-28-0

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

溶解性数据

In Vitro:

DMSO : 125 mg/mL(231.62 mM;Need ultrasonic)

配制储备液

浓度溶剂体积质量

1 mg

5 mg

10 mg

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。