8v5i
From Proteopedia
Crystal structure of 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 PubMedBy virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis. The resulting advanced lead compounds enabled a tumor growth inhibition study which was pivotal in assessing the potential value of MASTL as an oncology therapeutic target. Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL).,Gallego RA, Scales S, Toledo C, Auth M, Bernier L, Berry M, Brun S, Chung L, Davis C, Diehl W, Dress K, Eisele K, Elleraas J, Ewanicki J, Fobian Y, Greasley S, Greenwald EC, Johnson TW, Khamphavong P, Lafontaine J, Li J, Linton A, Maestre M, Miller N, Murtaza A, Patman RL, Quinlan CL, Ramms DJ, Richardson P, Sach N, Salomon-Ferrer R, Silva F, Timofeevski S, Tran P, Tran-Dube M, Wang F, Wang W, Wythes M, Yang S, Zou A, VanArsdale T, McAlpine I J Med Chem. 2024 Nov 14;67(21):19234-19246. doi: 10.1021/acs.jmedchem.4c01659. , Epub 2024 Nov 5. PMID:39499084[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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