5k00
From Proteopedia
MELK in complex with NVS-MELK5
Structural highlights
DiseaseMELK_HUMAN Note=Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor-initiating cells and proliferation via its function in cell proliferation regulation. FunctionMELK_HUMAN Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedWhile adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improving the kinase selectivity of type II maternal embryonic leucine zipper kinase inhibitors by applying these two complementary approaches together, which clearly demonstrates the powerful synergy between them. "Addition" and "Subtraction": Selectivity Design for Type II Maternal Embryonic Leucine Zipper Kinase Inhibitors.,Chen X, Giraldes J, Sprague ER, Shakya S, Chen Z, Wang Y, Joud C, Mathieu S, Chen CH, Straub C, Duca J, Hurov K, Yuan Y, Shao W, Toure BB J Med Chem. 2017 Feb 24. doi: 10.1021/acs.jmedchem.7b00033. PMID:28186750[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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