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== Publication Abstract from PubMed ==

Pyruvate kinase (PK) is the enzyme that catalyzes the conversion of phosphoenolpyruvate and adenosine diphosphate (ADP) to pyruvate and adenosine triphosphate (ATP) in glycolysis and plays a crucial role in regulating cell metabolism. 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 muM) and a panel of mutated PK proteins (K410E [AC50=0.0043 muM] and R510Q [AC50=0.0069 muM]), (2) displayed a significantly longer half-time of activation (&gt;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.

Structure-Based Design of AG-946, a Pyruvate Kinase Activator.,Liu T, Padyana AK, Judd ET, Jin L, Hammoudeh D, Kung C, Dang L ChemMedChem. 2023 Dec 18:e202300559. doi: 10.1002/cmdc.202300559. PMID:38109501<ref>PMID:38109501</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

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