Gandotinib(LY-2784544)

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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:	1229236-86-5
规格:	≥98%

包装与价格：

包装	价格(元)
5mg	电议
25mg	电议
50mg	电议
100mg	电议
250mg	电议
500mg	电议

产品介绍

理化性质和储存条件

Molecular Weight (MW)	469.94
Formula	C23H25ClFN7O
CAS No.	1229236-86-5
Storage	-20℃ for 3 years in powder form
Storage	-80℃ for 2 years in solvent
Solubility (In vitro)	DMSO: 94 mg/mL (200.0 mM)
	Water: <1 mg/mL
	Ethanol: 9 mg/mL (19.1 mM)
Other info	Chemical Name: 3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(3-methyl-1H-pyrazol-5-yl)-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine InChi Key: SQSZANZGUXWJEA-UHFFFAOYSA-N InChi Code: InChI=1S/C23H25ClFN7O/c1-14-9-21(29-28-14)27-22-11-17(13-31-5-7-33-8-6-31)23-26-15(2)20(32(23)30-22)10-16-3-4-18(24)12-19(16)25/h3-4,9,11-12H,5-8,10,13H2,1-2H3,(H2,27,28,29,30) SMILES Code: CC1=NNC(NC2=NN3C(C(CN4CCOCC4)=C2)=NC(C)=C3CC5=CC=C(Cl)C=C5F)=C1
Synonyms	LY-2784544; Gandotinib; LY 2784544; LY2784544;

实验参考方法

In Vitro	In vitro activity: LY2784544 also inhibits IL-3-activated wild type JAK2 with IC50 of 2.26 μM. Similarly in the proliferation assay, LY2784544 shows antiproliferation activity in JAK2 V617F-driven cells with IC50 of 68 nM, compared to 1.36 μM in wild type JAK2-driven cells and 0.94 μM in JAK3-driven cells. Though biochemical assays do not reveal selectivity of LY2784544 for mutant JAK2V617F, LY2784544 shows higher selectivity for inhibition of JAK2-mediated signaling and induction of apoptosis in Ba/F3 cells expressing JAK2V617F than wild-type cells. Kinase Assay: LY2784544(gandotinib) is a potent JAK2 inhibitor with IC50 of 3 nM, effective in JAK2V617F(Ki=0.245 nM), 8- and 20-fold selective versus JAK1 and JAK3. Cell Assay: LY2784544 showed minimal inhibition of STAT5 phosphorylation at 50 and 200 nM concentrations in IL-3-stimulated Ba/F3 cells which express wild-type JAK2. LY2784544 significantly inhibited the cell proliferation of JAK2V617F-expressing cells with IC50 ＝55 nM. In JAK2V617F-expressing cells, LY2784544 induced apoptosis with EC50±s.d.of 113±0.023 nM measured by Caspase3/7-glo assays.
In Vivo	LY2784544 significantly inhibits STAT5 phosphorylation in Ba/F3-JAK2 V617F-GFP xenografts with a Threshold Effective Dose 50 (TED50) of 12.7 mg/kg. LY2784544 also reduces Ba/F3-JAK2 V617F-GFP tumor burden in the JAK2 V617F-induced MPN model with a TED50 of 13.7 mg/kg after oral treatment. LY2784544 has no effect on CD71/Ter119 positive erythroid progenitors in spleens of SCID mice after oral treatment.
Animal model	Mice
Formulation & Dosage	Dose- and time-dependent in vivo inhibition of JAK2V617F signaling is assessed by measuring inhibition of STAT5 phosphorylation in a mouse ascitic tumor model. Ba/F3-JAK2V617F-GFP cells (1×107) are implanted in the intraperitoneal cavity of severe combined immunodeficiency mice (SCID mice) and allowed to develop into ascitic tumors for 7 days. For dose-response studies (six animals/group), Gandotinib (LY2784544) is administered once by oral gavage (2.5, 5, 10, 20, 40, or 80 mg/kg), then 30 min later, ascitic tumor cells are collected, fixed, incubated for 2 h with Mouse-anti-pSTAT5 (pY694) Alexa Fluor 647 (1:10 dilution), and analyzed by flow cytometry. Time course studies are performed similarly, except the animals are treated with Gandotinib (LY2784544) at 20, 40 or 80 mg/kg and ascitic tumor cells collected at prespecified intervals of 0.25-6 h after dosing. Data are analyzed by the one-way analysis of variance, and Dunnett's test (α=0.05). Dose response data are analyzed with a four-parameter logistic curve-fitting program.
References	Blood Cancer J. 2013 Apr 12;3:e109.

生物活性

Inhibition of mutant JAK2 and IL-3-wild-type-JAK2-activated STAT5 phosphorylation by JAK2 inhibitors in Ba/F3 and HEK293T cells. Blood Cancer J. 2013 Apr 12;3:e109.

LY2784544 effectively inhibits JAK2V617F-STAT5 signaling in ascitic tumor cells from Ba/F3-JAK2V617F-GFP tumor-bearing mice. Blood Cancer J. 2013 Apr 12;3:e109.

Reduction of splenomegaly and Ba/F3-JAK2V617F-GFP-positive tumor cell burden in a JAK2V617-induced mouse hematologic disease model after treatment with LY2784544, twice daily, for 14 days. Blood Cancer J. 2013 Apr 12;3:e109.