A-770041 is an inhibitor of LCK kinase (IC50 = 0.147 ?M).1 It is selective for LCK over other Src family tyrosine kinases including Src, Fyn, Fgr, HCK, and Tie2 (IC50s = 9.05, 44.1, 14.1, 1.22, and >50 ?M, respectively). A-770041 induces dephosphorylation of LCK by SHP-1, inactivating LCK, in IgE/antigen-stimulated bone marrow-derived mast cells (BMMCs).2 It inhibits IL-2 production induced by an anti-CD3 antibody and phorbol 12-myristate 13-acetate in isolated human whole blood (EC50 = 80 nM) and by concanavalin A in rats.3 A-770041 (10 mg/kg) prevents acute rejection and increases graft survival in a rat model of heterotopic heart transplantation. It also inhibits the growth of CTV-1 human acute myeloid leukemia cells (IC50 = 224 nM) and sensitizes U2OSMR and KHOSR2 multidrug resistant human osteosarcoma cells to paclitaxel and doxorubicin .4,5
1.Burchat, A., Borhani, D.W., Calderwood, D.J., et al.Discovery of A-770041, a src-family selective orally active lck inhibitor that prevents organ allograft rejectionBioorg. Med. Chem. Lett.16(1)118-122(2006) 2.Chang, H.W., Kanegasaki, S., Jin, F., et al.A common signaling pathway leading to degranulation in mast cells and its regulation by CCR1-ligandAllergy75(6)1371-1381(2020) 3.Stachlewitz, R.F., Hart, M.A., Bettencourt, B., et al.A-770041, a novel and selective small-molecule inhibitor of Lck, prevents heart allograft rejectionJ. Pharmacol. Exp. Ther.315(1)36-41(2005) 4.Li, L., Cui, Y., Shen, J., et al.Evidence for activated Lck protein tyrosine kinase as the driver of proliferation in acute myeloid leukemia cell, CTV-1Leuk. Res.7812-20(2019) 5.Duan, Z., Zhang, J., Ye, S., et al.A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cellsBMC Cancer14681(2014)