MON-239 Relief of CoA Sequestration by PANKs Agonist As a Potential Treatment for Acidemias

Abstract Disclosure: K. Zhang: None. J. Zhao: None. Y. Xia: None. W. Zhai: None. F. Yang: None. Methylmalonic acidemia (MMA), an autosomal recessive disorder, is characterized by increased levels of propionyl carnitine (C3) and methylmalonic acid in the blood, urine, and other body fluids that result from the failure to convert the methylmalonyl-coenzyme (CoA) into succinyl-CoA during propionate metabolism in the mitochondrial matrix. This disorder is usually caused by MMUT gene mutation resulting a complete or partial deficiency of methylmalonyl CoA mutates. Similarly, propionic acidemia (PA) is caused by a mutation in propionyl-CoA carboxylase. The accumulation of various acid metabolites reduces the concentrations of nonesterified coenzyme A(CoASH), thus compromising mitochondrial function and disrupting intermediary metabolism. The cellular total CoA concentration is controlled by the activities of three separately encoded pantothenate kinases (PANK1α, β; PANK2, and PANK3) that catalyze the first and rate-controlling step in CoASH biosynthesis. A PANK agonist BBP-671 is reported to be active in a PA model, even though its clinical development has been halted due to serious PK variations in human. Here, we report the identification and pharmacological characterization of a potent PANK agonist GSC003896 which could increase the CoASH and balance the metabolism in preclinical studies. In vitro, GSC003896 strongly activates PANK1 and PANK3 enzymes, superior to BBP-671. More importantly, the bell shape curve as observed from BBP-671 is not obvious with GSC003896. In vivo, in a MUT (p.M698K/M698K) mutation mouse model, both elevated plasma C3:C2-carnitine ratio and methylcitrate, hall mark biomarkers of MMA, are significantly reduced by oral dosing of GenSci compounds across various dosages. Moreover GSC003896 could further reduce C3:C2 ratio, comparing to BBP-671. GenSci compounds exhibit a favorable ADME profiles and are under active IND-enabling study. Presentation: Monday, July 14, 2025