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

Abstract

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.