Background
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)
Protocol
Cell experiment: | HUVECs are maintained in EGM2 media at 37°C and 5% CO2. HUVECs or peritoneal macrophages are treated with vehicle or PF-06260933 in vitro to determine whether pharmacological inhibition of MAP4K4 alteres MAPK signalling in response to TNF-α[2]. |
Animal experiment: | Compound PF-06260933 (10?mg/kg, dissolved in dH2O) is orally administered to 8 to 10-week-old male Apoe-/- mice twice daily for 6 weeks. Ldlr-/- male mice are placed on high-fat diet (HFD) for 10 weeks before drug administration. Compound PF-06260933 is administered to male 8 to 10-week-old Ldlr-/- mice as above for 10 weeks. Oral administration of water is used as vehicle control in all studies. Mice are euthanized by CO2 inhalation followed by bilateral pneumothorax[2]. |
参考文献: [1]. Ammirati M, et al. Discovery of an in Vivo Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment. ACS Med Chem Lett. 2015 Oct 6;6(11):1128-33.
[2]. Roth Flach RJ, et al. Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis. Nat Commun. 2015 Dec 21;6:8995. |
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