A-770041

Short Summary : Selective Lck inhibitor

Category : Tyrosine Kinase|Src

Purity : 0.98

CAS Number : 869748-10-7

Formula : C34H39N9O3

Molecular Weight : 621.75

SMILE : CC(=O)N1CCN(CC1)C2CCC(CC2)N3C4=C(C(=N3)C5=CC(=C(C=C5)NC(=O)C6=CC7=CC=CC=C7N6C)OC)C(=NC=N4)N

Solubility : DMSO

Storage : Store at -20°C

Description : The src-family of tyrosine kinases comprises eight highly homologous proteins that are primarily expressed in hematopoietic tissues, two of which, lck and fyn, are expresse in T cells. Lck plays a critical function during the initial steps of T-cell-receptor signaling resulting in a cascade of downstream signaling pathways. A-770041 is an orally bioavailable pyrazolo[3,4-d]pyrimidine exhibiting selectivity for Lck compared with previously reported compounds.In vitro: A-770041 is a 147 nM inhibitor of Lck (1 mM ATP) and is 300-fold selective against Fyn when compoared with the other involved Src family kinase. It was found that concanavalin A-stimulated IL-2 production in whole blood could be inhibited by A-770041 with an EC50 of approximately 80 nM [1]. In vivo: A-770041 is orally bioavailable (F = 34.1 ± 7.2% at 10 mg/kg) and has a t1/2 of 4.1 ± 0.1 h. Concanavalin A-induced IL-2 production in vivo is inhibited by oral administration of A-770041 (in vivo EC50 = 78 ± 28 nM). Doses of A-770041 at or above 10 mg/kg/day prevent rejection of hearts transplanted heterotopically in rats from Brown Norway donors to Lewis recipients across a major histocompatibility barrier for least 65 days. Moreover, grafts from animals treated with 20 mg/kg/day A-770041 or 10 mg/day Cyclosporin A had minimal microvascular changes or multifocal mononuclear infiltrates. In contract, mineralization in myocytes from the grafts from A-770041-treated animals was less than animals treated with Cyclosporin A [1]. Clinical trial: A-770041 is currently in the preclinical developlent stage and no clinical data are available.Reference:[1] Stachlewitz RF, Hart MA, Bettencourt B, Kebede T, Schwartz A, Ratnofsky SE, Calderwood DJ, Waegell WO, Hirst GC. A-770041, a novel and selective small-molecule inhibitor of Lck, prevents heart allograft rejection. J Pharmacol Exp Ther. 2005;315(1):36-41.

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