1. Structure–Activity Relationship Study of Covalent Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors
- Author
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Fleur M. Ferguson, Hyeseok Shim, Adam Yasgar, Min Shen, Matthew D. Hall, Sirano Dhe-Paganon, Nathanael S. Gray, Scott B. Ficarro, Jarrod A. Marto, Sindhu Carmen Sivakumaren, Joseph D. Card, Matthew B. Boxer, Theresa D. Manz, Anton Simeonov, Atsuo T. Sasaki, Hyuk-Soo Seo, Mindy I. Davis, Tinghu Zhang, and Lewis C. Cantley
- Subjects
010405 organic chemistry ,Kinase ,Chemistry ,Drug discovery ,Organic Chemistry ,Context (language use) ,01 natural sciences ,Biochemistry ,Small molecule ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Covalent bond ,Drug Discovery ,Structure–activity relationship ,Phosphatidylinositol ,Phosphatidylinositol 5-phosphate - Abstract
[Image: see text] 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.
- Published
- 2019