| Literature DB >> 32184968 |
Theresa D Manz1,2,3, Sindhu C Sivakumaren1,2, Adam Yasgar4, Matthew D Hall4, Mindy I Davis4, Hyuk-Soo Seo1,2, Joseph D Card5,6,7, Scott B Ficarro5,6,7, Hyeseok Shim8, Jarrod A Marto5,6,7, Sirano Dhe-Paganon1,2, Atsuo T Sasaki9, Matthew B Boxer4, Anton Simeonov4, Lewis C Cantley8, Min Shen4, Tinghu Zhang1,2, Fleur M Ferguson1,2, Nathanael S Gray1,2.
Abstract
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.Entities:
Year: 2019 PMID： 32184968 PMCID： PMC7074221 DOI： 10.1021/acsmedchemlett.9b00402
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345