2. Academic Validation
  3. Carboxylic Acid Bioisosteres of Creatine as Novel and Selective Substrate Competitive Inhibitors of the Creatine Transporter SLC6A8

Carboxylic Acid Bioisosteres of Creatine as Novel and Selective Substrate Competitive Inhibitors of the Creatine Transporter SLC6A8

  • J Med Chem. 2026 Feb 26;69(4):3915-3931. doi: 10.1021/acs.jmedchem.5c02607.
Eduardo J Martinez 1,  Darren H Wong 1,  Amish J Patel 1,  Roy J Vaz 2,  Robert W Busby 1,  Robert Zahler 1,  Daniel Schefer 1,  Hui Zhao 3,  Xiaoming Xu 3,  Zizhao Liu 3,  Ruifang Meng 3,  Bernd Kaiser 4,  Jianchao Liu 3,  Lei Wen 3,  Rui Liu 3,  Katya Leites 1,  Helen S Tian 5,  Sohail F Tavazoie 5,  Masoud F Tavazoie 1,  Isabel Kurth 1
Affiliations

Affiliations

  • 1 Inspirna, Inc.30-02 48th Avenue, Suite 350, Long Island City, New York 11101, United States.
  • 2 Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, California 94158, United States.
  • 3 Pharmaron Beijing Co., Ltd. 6, Taihe Road, BDA, Beijing 100176, P.R. of China.
  • 4 Escientia Life Sciences, LLC, 250 Nutmeg Road South, Unit N, South Windsor, Connecticut 06074, United States.
  • 5 The Rockefeller University1230 York Ave, New York, New York 10065, United States.
PMID: 41649519 DOI: 10.1021/acs.jmedchem.5c02607
Abstract

Creatine, a naturally occurring guanidine carboxylic acid, serves as a critical energy metabolite in tissues with high energy demands. Certain cancers upregulate creatine metabolism to supplement their energy needs. Ompenaclid, a salt form of the well-studied creatine transporter inhibitor 3-guanidinopropionic acid (β-GPA), is in clinical development for the treatment of patients with colorectal tumors. Existing SLC6A8 inhibitors are low-potency molecules and frequently interact with related transporters. Herein, we report the discovery of SLC6A8 inhibitors with increased selectivity as well as in vitro and in vivo potency. A bioisostere approach was used by replacing the carboxylic acid of β-GPA with surrogate functional groups to achieve these improvements. Docking of these inhibitors into the recently published SLC6A8 cryo-EM structure reveals key binding contacts and supports the observed structure-activity relationships.

Figures
Products