6OSP

Crystal Structure Analysis of PIP4K2A

Summary for 6OSP

• Entry DOI: 10.2210/pdb6osp/pdb
• Descriptor: Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha, 4-{[(2E)-4-(dimethylamino)but-2-enoyl]amino}-N-(3-{[6-(1H-indol-3-yl)pyrimidin-4-yl]amino}phenyl)benzamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: kinase, signaling protein, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 91713.41

Authors

Seo, H.-S.,Dhe-Paganon, S. (deposition date: 2019-05-01, release date: 2020-04-29, Last modification date: 2023-10-11)

Primary citation

Sivakumaren, S.C.,Shim, H.,Zhang, T.,Ferguson, F.M.,Lundquist, M.R.,Browne, C.M.,Seo, H.S.,Paddock, M.N.,Manz, T.D.,Jiang, B.,Hao, M.F.,Krishnan, P.,Wang, D.G.,Yang, T.J.,Kwiatkowski, N.P.,Ficarro, S.B.,Cunningham, J.M.,Marto, J.A.,Dhe-Paganon, S.,Cantley, L.C.,Gray, N.S.
Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors.
Cell Chem Biol, 27:525-, 2020

PubMed Abstract: The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here, we present the discovery and characterization of a pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K's reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.

PubMed: 32130941
DOI: 10.1016/j.chembiol.2020.02.003

Experimental method

X-RAY DIFFRACTION (2.21 Å)