Design, Synthesis, and Biological Evaluation of 3,4-Dihydroisoquinolin-1(<i>2H</i>)-one Derivatives as Protein Arginine Methyltransferase 5 Inhibitors for the Treatment of Non-Hodgkin’s Lymphoma
Through catalyzing the transfer of methyl groups onto the guanidinium of arginine, protein arginine methyltransferase 5 (PRMT5) was essential to the cell growth of cancer cells. By utilizing a scaffold hopping strategy, a novel series of 3,4-dihydroisoquinolin-1(<i>2H</i>)-one derivatives were designed and synthesized. Through a systematic SAR study, <b>D3</b> demonstrated excellent PRMT5 inhibitory activity, potent antiproliferative activity against Z-138, favorable pharmacokinetic profiles, and low hERG toxicity. Molecular docking, molecular dynamic (MD) simulation, and surface plasmon resonance (SPR) study indicated that <b>D3</b> was tightly interacted with PRMT5. Meanwhile, <b>D3</b> exhibited high selectivity against PRMT5, which could inhibit the growth of various cancer cells, induce apoptosis, and arrest the cell cycle in the G0/G1 phase. Additionally, <b>D3</b> possessed excellent antitumor efficacy in Z-138 xenograft models, low toxicity <i>in vivo</i>, and acceptable drug metabolism and pharmacokinetics (DMPK) profiles <i>in vitro</i>. Therefore, <b>D3</b> can be developed as a promising candidate for the treatment of non-Hodgkin's lymphoma (NHL).
Authors
- Q. L. Niu (ORCID: https://orcid.org/0000-0003-0015-3341)
- Xiaoting Liang (ORCID: https://orcid.org/0000-0003-3262-1859)
- Mingyu Bai (ORCID: https://orcid.org/0009-0001-8327-0422)
- Shan‐Liang Sun (ORCID: https://orcid.org/0000-0001-7011-6146)
- Peng Cao (ORCID: https://orcid.org/0000-0002-2044-3074)
- Shuangshuang Zhou
- Yan‐Cheng Yu (ORCID: https://orcid.org/0000-0002-9783-775X)
- Jian Liu (ORCID: https://orcid.org/0000-0001-9482-9036)
- Xinlei Tian (ORCID: https://orcid.org/0000-0001-5662-8874)
- Guochuang Zheng
- Zhi‐Hao Shi (ORCID: https://orcid.org/0000-0002-6827-9533)
- Qian Liu (ORCID: https://orcid.org/0000-0002-8078-1075)
- Xiaomeng Zhang (ORCID: https://orcid.org/0000-0002-3794-6823)
- Zixuan Wang (ORCID: https://orcid.org/0009-0007-8289-1538)
- Qingqing Li (ORCID: https://orcid.org/0000-0003-3043-921X)
- Quan Xu (ORCID: https://orcid.org/0009-0005-3964-9696)
- Yun Zhou (ORCID: https://orcid.org/0000-0002-7466-4593)
- Ke Zhan (ORCID: https://orcid.org/0000-0001-9504-6500)
- Jin Yang (ORCID: https://orcid.org/0000-0002-5337-487X)
- Xiaolong Jing (ORCID: https://orcid.org/0009-0006-6665-9678)
- Nian‐Guang Li
- Yujing Xu (ORCID: https://orcid.org/0009-0006-5969-8134)
- Xing-Feng Ni
- Tian‐Hua Wei
- Z Zhao (ORCID: https://orcid.org/0009-0004-9833-3504)
Institutions
- Nanjing University of Chinese Medicine (CN)
- China Pharmaceutical University (CN)
- Shanghai Innovative Research Center of Traditional Chinese Medicine (CN)
- Simcere Pharmaceutical (China) (CN)
- Integrated Chinese Medicine (China) (HK)
- Kangmei Pharmaceutical (China) (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-26
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01548
- Citations
- 6
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Jiangsu Province
- Nanjing University of Chinese Medicine
- State Key Laboratory of Natural Medicines
- National Key Research and Development Program of China