8v5h
Crystal structure of MASTL Kinase domain in complex with an inhibitorCrystal structure of MASTL Kinase domain in complex with an inhibitor
Structural highlights
DiseaseGWL_HUMAN Autosomal thrombocytopenia with normal platelets. The disease is caused by mutations affecting the gene represented in this entry. FunctionGWL_HUMAN Serine/threonine kinase that plays a key role in M phase by acting as a regulator of mitosis entry and maintenance. Acts by promoting the inactivation of protein phosphatase 2A (PP2A) during M phase: does not directly inhibit PP2A but acts by mediating phosphorylation and subsequent activation of ARPP19 and ENSA at 'Ser-62' and 'Ser-67', respectively. ARPP19 and ENSA are phosphatase inhibitors that specifically inhibit the PPP2R2D (PR55-delta) subunit of PP2A. Inactivation of PP2A during M phase is essential to keep cyclin-B1-CDK1 activity high. Following DNA damage, it is also involved in checkpoint recovery by being inhibited. Phosphorylates histone protein in vitro; however such activity is unsure in vivo. May be involved in megakaryocyte differentiation.[1] [2] [3] [4] [5] 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[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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