2. Academic Validation
  3. Metabolism-guided development of Ko143 analogs as ABCG2 inhibitors

Metabolism-guided development of Ko143 analogs as ABCG2 inhibitors

  • Eur J Med Chem. 2023 Jul 20;259:115666. doi: 10.1016/j.ejmech.2023.115666.
Junjie Zhu 1,  Saifei Lei 1,  Jie Lu 1,  Yixuan Hao 2,  Qi Qian 1,  Aaron S Devanathan 3,  Zhiwei Feng 2,  Xiang-Qun Xie 2,  Peter Wipf 4,  Xiaochao Ma 5
Affiliations

Affiliations

  • 1 Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
  • 2 Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA, USA.
  • 3 Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
  • 4 Department of Chemistry and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5 Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: mxiaocha@pitt.edu.
PMID: 37482017 DOI: 10.1016/j.ejmech.2023.115666
Abstract

ATP-binding cassette subfamily G member 2 (ABCG2), an efflux transporter, is involved in multiple pathological processes. Ko143 is a potent ABCG2 inhibitor; however, it is quickly metabolized through Carboxylesterase 1-mediated hydrolysis of its t-butyl ester moiety. The current work aimed to develop more metabolically stable ABCG2 inhibitors. Novel Ko143 analogs were designed and synthesized by replacing the unstable t-butyl ester moiety in Ko143 with an amide group. The synthesized Ko143 analogs were evaluated for their ABCG2 inhibitory activity, binding mode with ABCG2, cytotoxicity, and metabolic stability. We found that the amide modification of Ko143 led to metabolically stable ABCG2 inhibitors. Among these Ko143 analogs, K2 and K34 are promising candidates with favorable oral pharmacokinetic profiles in mice. In summary, we synthesized novel Ko143 analogs with improved metabolic stability, which can potentially be used as lead compounds for the future development of ABCG2 inhibitors.

Keywords

ABCG2 inhibitor; Carboxylesterase; Ko143 analogs; Metabolic stability; Pharmacokinetics.

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