Structure-Based Design of AG-946, a Pyruvate Kinase Activator

We describe the structure-based design of compound 27 (AG-946), an activator of PK isoforms, including red blood cell (RBC)-specific isoforms of PK (PKR), designed to have a pseudo-C2-symmetry matching its allosteric binding site on the PK enzyme, which increased its potency towards PKR while reducing activity against off-targets observed from the original scaffold. Compound 27 (AG-946) demonstrated (1) activation of human wild-type PK (half maximal activation concentration [AC50]=0.005 μM) and a panel of mutated PK proteins (K410E [AC50=0.0043 μM] and R510Q [AC50=0.0069 μM]), (2) displayed a significantly longer half-time of activation (>150-fold) compared with compound 2, and (3) stabilized PKR R510Q, an unstable mutant PKR enzyme, and preserved its catalytic activity under increasingly denaturing conditions. Compound 27 was advanced to human clinical trial as AG-946, a potent, investigational, oral small-molecule allosteric activator of wild-type and mutant PKR.PMID:38109501 | DOI:10.1002/cmdc.202300559
Source: ChemMedChem - Category: Chemistry Authors: Source Type: research