Design, Synthesis and Biological Evaluation of New TRPM7 Channel Inhibitors as Potential Therapeutics for Breast Cancer

  • J Med Chem. 2026 Oct 8;69(19):22208-22230. doi: 10.1021/acs.jmedchem.6c01359.
Naining Zhang  1  2 ,  Sayuri Suzuki  3  4 ,  Yiping Gao  1  2 ,  Yang Lin  1  2  5 ,  Qingjia Guo  1  2 ,  Chaojin Si  1  2 ,  Chengchun Zhu  1  2 ,  Xiaoyu Liu  6 ,  Kai Chen  6 ,  Andrea Fleig  3  7 ,  Reinhold Penner  3  7 ,  Zhiyi Yu  1  2
Affiliations
  • 1. Department of Medicinal Chemistry, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong250012, P. R. China.
  • 2. Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong250012, P. R. China.
  • 3. Center for Biomedical Research, The Queen's Medical Center, Honolulu, Hawaii96813, United States.
  • 4. College of Natural and Computational Sciences, Hawaii Pacific University, Honolulu, Hawaii96813, United States.
  • 5. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu221004, P. R. China.
  • 6. Center for New Drug Evaluation, Shandong Academy of Pharmaceutical Sciences, Jinan, Shandong250000, P. R. China.
  • 7. John A. Burns School of Medicine & University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii96813, United States.
PMID: 42917899 DOI: 10.1021/acs.jmedchem.6c01359
Abstract

TRPM7 channel is a critical regulator of cellular divalent cation homeostasis and a validated driver of Cancer progression. Despite its therapeutic relevance, currently available TRPM7 inhibitors are limited in number and modest in potency with no TRPM7-targeted agents having advanced to clinical application. Herein, we report the structure-guided design and synthesis of a series of 2-aminobenzimidazole analogues based on NS8593, leading to the identification of two potent TRPM7 inhibitors, SDUY212 and SDUY225, that demonstrated robust electrophysiological inhibitory activity against TRPM7. Both compounds effectively suppressed the proliferation, migration and invasion of MCF-7 and MDA-MB-231 Breast Cancer cells while inducing Apoptosis and cell-cycle arrest. Furthermore, SDUY212 exhibited significant antitumor efficacy in a MCF-7 xenograft model. Mechanistically, TRPM7 inhibition attenuated EGF-induced STAT3 phosphorylation, thereby suppressing Cancer cell migration and invasion. Collectively, these findings identify SDUY212 and SDUY225 as potent TRPM7 inhibitors and promising lead compounds for the rational development of TRPM7-targeted Anticancer therapeutics.

Keywords
STAT3; TRPM7; antitumor activity; breast cancer; channel inhibitor.
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