Discovery of novel BCAT2 inhibitors: design, synthesis, in vitro evaluation, and molecular modeling studies

Branched-chain amino acid transaminase 2 (BCAT2) is a promising therapeutic target for metabolic diseases and cancers such as pancreatic ductal adenocarcinoma. In this study, we report the discovery of novel and potent inhibitors against this enzyme. Through a structure-based strategy integrating scaffold hopping, core simplification, and hydrophobic cavity filling, three series of compounds (A, B, and C) were designed and synthesized. Several compounds in series C exhibited nanomolar inhibitory potency (C10, IC₅₀ = 44 nM; C11, IC₅₀ = 54 nM). Key structure-activity relationships were elucidated, highlighting the critical roles of the aromatic core, the polar substituent at the 2-position, and occupation of the upper hydrophobic pocket in enhanced activity. Molecular docking and dynamics simulations predict that the compounds bind stably to the BCAT2 active site, engaging in persistent π-π stacking and hydrogen-bonding networks with key residues such as Phe-30 and Tyr-173. This work provides valuable lead compounds and structural insights into the development of highly potent and selective BCAT2 inhibitors.