Hongfeng Deng; Jingye Zhou; Flora S. Sundersingh; Jennifer Summerfield; Don Somers; Jeffrey A. Messer; Alexander L. Satz; Nicolas Ancellin; Christopher C. Arico-Muendel; Katie L. (Sargent) Bedard; Arthur Beljean; Svetlana L. Belyanskaya; Ryan Bingham; Sarah E. Smith; Eric Boursier; Paul Carter; Paolo A. Centrella; Matthew A. Clark; Chun-wa Chung; Christopher P. Davie; Jennifer L. Delorey; Yun Ding; G. Joseph Franklin; LaShadric C. Grady; Kenny Herry; Clare Hobbs; Christopher S. Kollmann; Barry A. Morgan; Laura J. (Pothier) Kaushansky; Quan Zhou
ACS Med. Chem. Lett., 2015, 6, 8, 919-924
https://doi.org/10.1021/acsmedchemlett.5b00179

Abstract

As a potential target for obesity, human BCATm was screened against more than 14 billion DNA encoded compounds of distinct scaffolds followed by off-DNA synthesis and activity confirmation. As a consequence, several series of BCATm inhibitors were discovered. One representative compound (R)-3-((1-(5-bromothiophene-2-carbonyl)pyrrolidin-3-yl)oxy)-N-methyl-2'-(methylsulfonamido)-[1,1'-biphenyl]-4-carboxamide (15e) from a novel compound library synthesized via on-DNA Suzuki-Miyaura cross-coupling showed BCATm inhibitory activity with IC50 = 2.0 μM. A protein crystal structure of 15e revealed that it binds to BCATm within the catalytic site adjacent to the PLP cofactor. The identification of this novel inhibitor series plus the establishment of a BCATm protein structure provided a good starting point for future structure-based discovery of BCATm inhibitors.