6UX9

Crystal Structure Analysis of PIP4K2A

Summary for 6UX9

• Entry DOI: 10.2210/pdb6ux9/pdb
• Descriptor: 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)
• Functional Keywords: kinase, signaling protein, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 86490.21

Authors

Seo, H.-S.,Dhe-Paganon, S. (deposition date: 2019-11-07, release date: 2020-12-09, Last modification date: 2023-10-11)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.71 Å)