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 13, 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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Manz TD,Sivakumaren SC,Ferguson FM,Zhang T,Yasgar A,Seo HS,Ficarro SB,Card JD,Shim H,Miduturu CV,Simeonov A,Shen M,Marto JA,Dhe-Paganon S,Hall MD,Cantley LC,Gray NSdoi
10.1021/acs.jmedchem.0c00227subject
Has Abstractpub_date
2020-05-14 00:00:00pages
4880-4895issue
9eissn
0022-2623issn
1520-4804journal_volume
63pub_type
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