Saturday, November 9, 2019

Structure–Activity Relationship Study of Covalent Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors

Theresa D. ManzSindhu C. SivakumarenAdam YasgarMatthew D. HallMindy I. DavisHyuk-Soo SeoJoseph D. CardScott B. FicarroHyeseok ShimJarrod A. MartoSirano Dhe-PaganonAtsuo T. SasakiMatthew B. BoxerAnton SimeonovLewis C. CantleyMin ShenTinghu ZhangFleur M. Ferguson, and Nathanael S. Gray

ACS Medicinal Chemistry Letters  2019DOI: 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.

Covalent drug discovery using sulfur(VI) fluoride exchange warheads

Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 Covalent drug discovery has ...