Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kα.

ABSTRACT: Covalent protein kinase inhibitors exploit currently noncatalytic cysteines in the adenosine 5'-triphosphate (ATP)-binding site via electrophiles directly appended to a reversible-inhibitor scaffold. Here, we delineate a path to target solvent-exposed cysteines at a distance >10 Å from an ATP-site-directed core module and produce potent covalent phosphoinositide 3-kinase α (PI3Kα) inhibitors. First, reactive warheads are used to reach out to Cys862 on PI3Kα, and second, enones are replaced with druglike warheads while linkers are optimized. The systematic investigation of intrinsic warhead reactivity (k_chem), rate of covalent bond formation and proximity (k_inact and reaction space volume V_r), and integration of structure data, kinetic a

SUBMITTER: Borsari C 

PROVIDER: S-EPMC9011356 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature