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

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

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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