Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma

  • J Med Chem. 2024 Apr 25;67(8):6313-6326. doi: 10.1021/acs.jmedchem.3c02265.
Zhihao Liu  1 ,  Min Lin  1 ,  Chenyu Liu  2 ,  Xin Chen  1 ,  Qian Chen  1 ,  Xinyu Li  3 ,  Xiaoyan Wu  3 ,  Yahui Wang  4 ,  Lei Wang  1 ,  Fan Yang  2 ,  Cheng Luo  3  5 ,  Jia Jin  1 ,  Fei Ye  1
Affiliations
  • 1. College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China.
  • 2. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, China.
  • 3. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310000, China.
  • 4. Department of Anesthesiology, the First Affiliated Hospital of Bengbu Medical College, No. 287 Changhuai Road, Bengbu City 233000, China.
  • 5. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 38574345 DOI: 10.1021/acs.jmedchem.3c02265
Abstract

Coactivator-associated arginine methyltransferase 1 (CARM1), an important member of type I protein arginine methyltransferases (PRMTs), has emerged as a promising therapeutic target for various Cancer types. In our previous study, we have identified a series of type I PRMT inhibitors, among which ZL-28-6 (6) exhibited increased activity against CARM1 while displaying decreased potency against Other type I PRMTs. In this work, we conducted chemical modifications on compound 6, resulting in a series of (2-(benzyloxy)phenyl)methanamine derivatives as potent inhibitors of CARM1. Among them, compound 17e displayed remarkable potency and selectivity for CARM1 (IC50 = 2 ± 1 nM), along with notable antiproliferative effects against melanoma cell lines. Cellular thermal shift assay and western blot experiments confirmed that compound 6 effectively targets CARM1 within cells. Furthermore, compound 17e displayed good antitumor efficacy in a melanoma xenograft model, indicating that this compound warrants further investigation as a potential Anticancer agent.

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