Bicyclic Inhibitors of Branched-Chain α-Keto Acid Dehydrogenase Kinase (BDK) with In Vivo Activity

Jue Liang; Xiaoyu Wang; Francisco Ortiz; Gauri Shishodia; Tian Liu; Chen Gao; Noelle S Williams; David T Chuang; R Max Wynn; Joseph M Ready

doi:10.1021/acsmedchemlett.4c00362

Bicyclic Inhibitors of Branched-Chain α-Keto Acid Dehydrogenase Kinase (BDK) with In Vivo Activity

ACS Med Chem Lett. 2024 Oct 28;15(11):1899-1906. doi: 10.1021/acsmedchemlett.4c00362. eCollection 2024 Nov 14.

Authors

Affiliations

¹ Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-9038, United States.
² Department of Pharmacology and Systems Physiology, University of Cincinnati, 3230 Eden Avenue, Cincinnati, Ohio 45267, United States.

PMID: 39563832
PMCID: PMC11571092 (available on 2025-11-14)
DOI: 10.1021/acsmedchemlett.4c00362

Abstract

Elevated levels of the branched chain α-amino acids valine, leucine, and isoleucine are associated with heart disease and metabolic disorders. The kinase BDK, also known as branched-chain ketoacid dehydrogenase kinase (BCKDK), is a negative regulator of branched-chain α-amino acid metabolism through deactivation of BCKDC, the branched-chain α-ketoacid dehydrogenase complex. Inhibitors of BDK increase the activity of BCKDC and could be useful therapeutic leads for cardiometabolic diseases. We describe a novel bicyclic carboxy amide as an inhibitor of BDK with in vivo activity.