Chemical Catalysis Guides Structural Identification for the Major In Vivo Metabolite of the BET Inhibitor JQ1

  • ACS Med Chem Lett. 2024 Jan 2;15(1):107-115. doi: 10.1021/acsmedchemlett.3c00464.
Secondra Holmes  1  2 ,  Prashi Jain  1  2 ,  Kenneth Guzman Rodriguez  1  2 ,  Jade Williams  1  2 ,  Zhifeng Yu  1  2 ,  Christian Cerda-Smith  1 ,  Errol L G Samuel  1 ,  James Campbell  1 ,  John Michael Hakenjos  1 ,  Diana Monsivais  1 ,  Feng Li  1 ,  Srinivas Chamakuri  1 ,  Martin M Matzuk  1 ,  Conrad Santini  1 ,  Kevin R MacKenzie  1  2 ,  Damian W Young  1  2
Affiliations
  • 1. Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 2. Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States.
PMID: 38229743 DOI: 10.1021/acsmedchemlett.3c00464
Abstract

The bromodomain inhibitor (+)-JQ1 is a highly validated chemical probe; however, it exhibits poor in vivo pharmacokinetics. To guide efforts toward improving its pharmacological properties, we identified the (+)-JQ1 primary metabolite using chemical catalysis methods. Treatment of (+)-JQ1 with tetrabutylammonium decatungstate under photochemical conditions resulted in selective formation of an aldehyde at the 2-position of the thiophene ring [(+)-JQ1-CHO], which was further reduced to the 2-hydroxymethyl analog [(+)-JQ1-OH]. Comparative LC/MS analysis of (+)-JQ1-OH to the product obtained from liver microsomes suggested (+)-JQ1-OH as the major metabolite of (+)-JQ1. The 2-thienyl position was then substituted to generate a trideuterated (-CD3, (+)-JQ1-D) analog having half-lives that were 1.8- and 2.8-fold longer in mouse and human liver microsomes, respectively. This result unambiguously confirmed (+)-JQ1-OH as the major metabolite of (+)-JQ1. These studies demonstrate an efficient process for studying drug metabolism and identifying the metabolic soft spots of bioactive compounds.

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