Structure-based discovery of potent CARM1 inhibitors for colorectal cancer therapy

  • Eur J Med Chem. 2024 Mar 4:269:116288. doi: 10.1016/j.ejmech.2024.116288.
Chenyu Liu  1 ,  Yang Li  1 ,  Zhihao Liu  2 ,  Chenxi Cao  3 ,  Min Lin  2 ,  Xin Chen  2 ,  Mengting Yuan  2 ,  Yaohua Fan  3 ,  Xiaodong Gu  3 ,  Lei Wang  2 ,  Fan Yang  4 ,  Fei Ye  5 ,  Jia Jin  6
Affiliations
  • 1. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
  • 2. College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China.
  • 3. Department of Oncology, The Second Affiliated Hospital of Jiaxing University, No. 397, Huangcheng North Road, Jiaxing, 314000, China.
  • 4. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China. Electronic address: [email protected].
  • 5. College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China. Electronic address: [email protected].
  • 6. College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China. Electronic address: [email protected].
PMID: 38460270 DOI: 10.1016/j.ejmech.2024.116288
Abstract

Coactivator-associated arginine methyltransferase 1 (CARM1) plays an important role in cell proliferation and gene expression, and is highly expressed in a variety of tumor tissues. Guided by our previous reported structure of DCPR049_12, we focused on designing and evaluating selective CARM1 inhibitors, resulting in the identification of compound 11f as a promising lead candidate. Compound 11f displayed potent inhibition of CARM1 (IC50 = 9 nM). Comprehensive evaluations, including in vitro metabolic stability assessments, molecular modelling, cellular studies, and in vivo anti-tumor studies, confirmed that it induced Cancer cell Apoptosis and specifically inhibited CARM1's methylation function. Notably, compound 11f displayed significant anti-proliferative effects on colorectal Cancer cell lines, showcasing its potential for targeted therapies against CARM1-related diseases. This study provides valuable insights for the future development of specific and effective CARM1 inhibitors.

Keywords
Antitumor; Arginine methyltransferase; Inhibitor; Methylate; PRMTs.
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