Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 3, Pages 346-352Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00402
Keywords
PI5P4K; lipid kinase inhibitors; structure-activity relationship; covalent inhibitors; phosphoinositide; drug discovery
Categories
Funding
- National Institutes of Health [R01 CA197329, R01 NS089815, R03 MH096575, R01 CA222218, R03 CA250020, R35 CA197588, R01 GM041890, U54 CA210184]
- Breast Cancer Research Foundation
- NIH intramural research program (NCATS)
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Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are important molecular players in a variety of diseases, such as cancer. Currently available PI5P4K inhibitors are reversible small molecules, which may lack selectivity and sufficient cellular on-target activity. In this study, we present a new class of covalent pan-PI5P4K inhibitors with potent biochemical and cellular activity. Our designs are based on THZ-P1-2, a covalent PI5P4K inhibitor previously developed in our lab. Here, we report further structure-guided optimization and structure-activity relationship (SAR) study of this scaffold, resulting in compound 30, which retained biochemical and cellular potency, while demonstrating a significantly improved selectivity profile. Furthermore, we confirm that the inhibitors show efficient binding affinity in the context of HEK 293T cells using isothermal CETSA methods. Taken together, compound 30 represents a highly selective pan-PI5P4K covalent lead molecule.
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