5di1
MAP4K4 in complex with an inhibitor
Structural highlights
FunctionM4K4_HUMAN Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha. Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322.[1] [2] Publication Abstract from PubMedRecent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance. Discovery of an in Vivo Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment.,Ammirati M, Bagley SW, Bhattacharya SK, Buckbinder L, Carlo AA, Conrad R, Cortes C, Dow RL, Dowling MS, El-Kattan A, Ford K, Guimaraes CR, Hepworth D, Jiao W, LaPerle J, Liu S, Londregan A, Loria PM, Mathiowetz AM, Munchhof M, Orr ST, Petersen DN, Price DA, Skoura A, Smith AC, Wang J ACS Med Chem Lett. 2015 Oct 6;6(11):1128-33. doi: 10.1021/acsmedchemlett.5b00215., eCollection 2015 Nov 12. PMID:26617966[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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