A-770041 - CAS 869748-10-7
Catalog number: 869748-10-7
Category: Inhibitor
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A-770041 is an selective and orally bioavailable pyrazolo[3,4-d]pyrimidine exhibiting selectivity for Lck compared with previously reported compounds. It is 300-fold selective against Fyn, the other Src family kinase involved in T-cell signaling. It is currently in the preclinical developlent stage and no clinical data are available.
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1.Discovery of A-770041, a src-family selective orally active lck inhibitor that prevents organ allograft rejection.
Burchat A1, Borhani DW, Calderwood DJ, Hirst GC, Li B, Stachlewitz RF. Bioorg Med Chem Lett. 2006 Jan 1;16(1):118-22. Epub 2005 Oct 10.
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.
2.A-770041, a novel and selective small-molecule inhibitor of Lck, prevents heart allograft rejection.
Stachlewitz RF1, Hart MA, Bettencourt B, Kebede T, Schwartz A, Ratnofsky SE, Calderwood DJ, Waegell WO, Hirst GC. J Pharmacol Exp Ther. 2005 Oct;315(1):36-41. Epub 2005 Jul 12.
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]pyrimidin-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.
3.A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cells.
Duan Z1, Zhang J, Ye S, Shen J, Choy E, Cote G, Harmon D, Mankin H, Hua Y, Zhang Y, Gray NS, Hornicek FJ. BMC Cancer. 2014 Sep 19;14:681. doi: 10.1186/1471-2407-14-681.
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.
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CAS 869748-10-7 A-770041

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