8TBS

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

(2024) ChemMedChem 19: e202300559-e202300559

• PubMed: 38109501 Search on PubMed
• DOI: https://doi.org/10.1002/cmdc.202300559
• Primary Citation of Related Structures:  
  8TBS, 8TBT, 8TBU


• PubMed Abstract: 
  

  Pyruvate kinase (PK) is the enzyme that catalyzes the conversion of phosphoenolpyruvate and adenosine diphosphate to pyruvate and adenosine triphosphate in glycolysis and plays a crucial role in regulating cell metabolism. We describe the structure-based design of AG-946, an activator of PK isoforms, including red blood cell-specific forms of PK (PKR). This was designed to have a pseudo-C2-symmetry matching its allosteric binding site on the PK enzyme, which increased its potency toward PKR while reducing activity against off-targets observed from the original scaffold. AG-946 (1) demonstrated activation of human wild-type PK (half-maximal activation concentration [AC ₅₀ ]=0.005?μM) and a panel of mutated PK proteins (K410E [AC ₅₀ =0.0043?μM] and R510Q [AC ₅₀ =0.0069?μM]), (2) displayed a significantly longer half-time of activation (>150-fold) compared with 6-(3-methoxybenzyl)-4-methyl-2-(methylsulfinyl)-4,6-dihydro-5H-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one, and (3) stabilized PKR R510Q, an unstable mutant PKR enzyme, and preserved its catalytic activity under increasingly denaturing conditions. As a potent, oral, small-molecule allosteric activator of wild-type and mutant PKR, AG-946 was advanced to human clinical trials.

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Organizational Affiliation: 

Ensem Therapeutics, 880 Winter St, Waltham, MA 02451, USA.