6UX9

Crystal Structure Analysis of PIP4K2A

6UX9 の概要

• エントリーDOI: 10.2210/pdb6ux9/pdb
• 分子名称: Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha, N-[4-(5-{(Z)-[(2E)-2-imino-4-oxo-1,3-thiazolidin-5-ylidene]methyl}pyridin-3-yl)phenyl]methanesulfonamide (3 entities in total)
• 機能のキーワード: kinase, signaling protein, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 86490.21

構造登録者

Seo, H.-S.,Dhe-Paganon, S. (登録日: 2019-11-07, 公開日: 2020-12-09, 最終更新日: 2023-10-11)

主引用文献

Manz, T.D.,Sivakumaren, S.C.,Ferguson, F.M.,Zhang, T.,Yasgar, A.,Seo, H.S.,Ficarro, S.B.,Card, J.D.,Shim, H.,Miduturu, C.V.,Simeonov, A.,Shen, M.,Marto, J.A.,Dhe-Paganon, S.,Hall, M.D.,Cantley, L.C.,Gray, N.S.
Discovery and Structure-Activity Relationship Study of ( Z )-5-Methylenethiazolidin-4-one Derivatives as Potent and Selective Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors.
J.Med.Chem., 63:4880-4895, 2020

PubMed Abstract: Due to their role in many important signaling pathways, phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive targets for the development of experimental therapeutics for cancer, metabolic, and immunological disorders. Recent efforts to develop small molecule inhibitors for these lipid kinases resulted in compounds with low- to sub-micromolar potencies. Here, we report the identification of CVM-05-002 using a high-throughput screen of PI5P4Kα against our in-house kinase inhibitor library. CVM-05-002 is a potent and selective inhibitor of PI5P4Ks, and a 1.7 Å X-ray structure reveals its binding interactions in the ATP-binding pocket. Further investigation of the structure-activity relationship led to the development of compound , replacing the rhodanine-like moiety present in CVM-05-002 with an indole, a potent pan-PI5P4K inhibitor with excellent kinome-wide selectivity. Finally, we employed isothermal cellular thermal shift assays (CETSAs) to demonstrate the effective cellular target engagement of PI5P4Kα and -β by the inhibitors in HEK 293T cells.

PubMed: 32298120
DOI: 10.1021/acs.jmedchem.0c00227

実験手法

X-RAY DIFFRACTION (1.71 Å)