Theresa D. Manz, Sindhu C. Sivakumaren, Adam Yasgar, Matthew D. Hall, Mindy I. Davis, Hyuk-Soo Seo, Joseph D. Card, Scott B. Ficarro, Hyeseok Shim, Jarrod A. Marto, Sirano Dhe-Paganon, Atsuo T. Sasaki, Matthew B. Boxer, Anton Simeonov, Lewis C. Cantley, Min Shen, Tinghu Zhang, Fleur M. Ferguson, and Nathanael S. Gray
ACS Medicinal Chemistry Letters 2019, DOI: 10.1021/acsmedchemlett.9b00402
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.