PF-06260933

PF-6260933 is an inhibitor of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4; IC₅₀ = 3.7 nM).¹ It is selective for MAP4K4 over a panel of 41 kinases at 1 ?M but also inhibits TRAF2- and NCK-interacting kinase (TNIK) and misshapen-like kinase 1 (MINK1; IC₅₀s = 15 and 8 nM, respectively). PF-6260933 inhibits the replication of CMV strains AD169 and Merlin(R1111) strains in human foreskin fibroblast (HFF) cells (EC₅₀s = 9.6 and 13.3 ?M, respectively).² It inhibits collagen- or thrombin-induced aggregation of isolated human platelets by 70.9 and 61.2%, respectively, when used at a concentration of 20 ?M.³ It decreases plaque formation in ApoE^-/- mice fed a Western diet in a model of atherosclerosis when administered at a dose of 10 mg/kg.⁴ PF-6260933 (15 mg/kg) decreases LPS-induced increases in TNF-α levels in wild-type mice and fasting blood glucose levels in ob/ob mice.¹

1.Ammirati, M., Bagley, S.W., Bhattacharya, S.K., et al.Discovery of an in vivo tool to establish proof-of-concept for MAP4K4-based antidiabetic treatmentACS Med. Chem. Lett.6(11)1128-1133(2015) 2.Strang, B.L., Asquith, C.R.M., Moshrif, H.F., et al.Identification of lead anti-human cytomegalovirus compounds targeting MAP4K4 via machine learning analysis of kinase inhibitor screening dataPLoS One13(7)e0201321(2018) 3.Nam, G.S., Kim, S., Kwon, Y.-S., et al.A new function for MAP4K4 inhibitors during platelet aggregation and platelet-mediated clot retractionBiochem. Pharmacol.188114519(2021) 4.Roth Flach, R.J., Skoura, A., Matevossian, A., et al.Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosisNat. Commun.68995(2015)