A-770041

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.

A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cells.[Pubmed:25236161]

BMC Cancer. 2014 Sep 19;14:681.

BACKGROUND: Reversing multidrug resistance (MDR) has been an important goal for clinical and investigational oncologists. In the last few decades, significant effort has been made to search for inhibitors to reverse MDR by targeting ATP-binding cassette (ABC) transporters (Pgp, MRP) directly, but these efforts have achieved little clinical success. Protein kinases play important roles in many aspects of tumor cell growth and survival. Combinations of kinase inhibitors and chemotherapeutics have been observed to overcome cancer drug resistance in certain circumstances. METHODS: We screened a kinase specific inhibitor compound library in human osteosarcoma MDR cell lines to identify inhibitors that were capable of reversing chemoresistance to doxorubicin and paclitaxel. RESULTS: We identified 18 small molecules that significantly increase chemotherapy drug-induced cell death in human osteosarcoma MDR cell lines U-2OSMR and KHOSR2. We identified A-770041 as one of the most effective MDR reversing agents when combined with doxorubicin or paclitaxel. A-770041 is a potent Src family kinase (Lck and Src) inhibitor. Western blot analysis revealed A-770041 inhibits both Src and Lck activation and expression. Inhibition of Src expression in U-2OSMR and KHOSR2 cell lines using lentiviral shRNA also resulted in increased doxorubicin and paclitaxel drug sensitivity. A-770041 increases the intracellular drug accumulation as demonstrated by calcein AM assay. CONCLUSIONS: These results indicate that small molecule inhibitor A-770041 may function to reverse ABCB1/Pgp-mediated chemotherapy drug resistance. Combination of Src family kinase inhibitor with regular chemotherapy drug could be clinically effective in MDR osteosarcoma.

A-770041, a novel and selective small-molecule inhibitor of Lck, prevents heart allograft rejection.[Pubmed:16014572]

J Pharmacol Exp Ther. 2005 Oct;315(1):36-41.

Lck, one of eight members of the Src family of tyrosine kinases, is activated after T cell stimulation and is required for T-cell proliferation and interleukin (IL)-2 production. Inhibition of Lck has been a target to prevent lymphocyte activation and acute rejection. Here, we report the pharmacologic characterization of 1-methyl-1H-indole-2-carboxylic acid (4-{1-[4-(4-acetyl-piperazin-l-yl)-cyclohexyl]-4-amino-1H-pyrazolo[3,4-d]pyrimidi n-3-yl}-2-methoxy-phenyl)-amide (A-770041), an orally bioavailable pyrazolo[3,4-d]pyrimidine with increased selectivity for Lck compared with previously reported compounds. A-770041 is a 147 nM inhibitor of Lck (1 mM ATP) and is 300-fold selective against Fyn, the other Src family kinase involved in T-cell signaling. Concanavalin A-stimulated IL-2 production in whole blood is inhibited by A-770041 with an EC50 of approximately 80 nM. A-770041 is orally bioavailable (F = 34.1 +/- 7.2% at 10 mg/kg) and has a t(1/2) 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. 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. However, mineralization in myocytes from the grafts from A-770041-treated animals was less than animals treated with Cyclosporin A. Lck inhibition is an attractive target to prevent acute rejection.

Discovery of A-770041, a src-family selective orally active lck inhibitor that prevents organ allograft rejection.[Pubmed:16216497]

Bioorg Med Chem Lett. 2006 Jan 1;16(1):118-22.

We describe the identification, SAR, and pharmacology of the src-family selective lck inhibitor A-770041 that prolongs the survival of major histocompatibility mismatched allografts in models of solid organ transplant rejection for greater than 65 days.

A-770041 is selective and orally active Src-family Lck inhibitor; A-770041 is a 147 nM inhibitor of Lck (1 mM ATP) and is 300-fold selective against Fyn, the other Src family kinase involved in T-cell signaling.

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