2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of 3,4-Dihydroisoquinolin-1(2H)-one Derivatives as Protein Arginine Methyltransferase 5 Inhibitors for the Treatment of Non-Hodgkin's Lymphoma

Design, Synthesis, and Biological Evaluation of 3,4-Dihydroisoquinolin-1(2H)-one Derivatives as Protein Arginine Methyltransferase 5 Inhibitors for the Treatment of Non-Hodgkin's Lymphoma

  • J Med Chem. 2025 Jan 9;68(1):108-134. doi: 10.1021/acs.jmedchem.4c01548.
Qing-Qing Li 1 2,  Xu Quan 2,  Zi-Xuan Wang 1,  Nuo Qiao 1,  Xing-Feng Ni 1,  Xiao-Long Jing 1,  Shuang-Shuang Zhou 1,  Xin-Lei Tian 2,  Guo-Chuang Zheng 2,  Kang-Ning Zhan 2,  Yu-Jing Xu 1,  Jin Yang 1,  Yun Zhou 1,  Xiao-Ting Liang 1,  Zong-Hao Zhao 1,  Tian-Hua Wei 1,  Qian Liu 1,  Ming-Yu Bai 1,  Shan-Liang Sun 1,  Yan-Cheng Yu 1,  Peng Cao 3,  Nian-Guang Li 1,  Xiao-Meng Zhang 2,  Jian Liu 1,  Zhi-Hao Shi 4
Affiliations

Affiliations

  • 1 National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 2 R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 211135, China.
  • 3 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China.
  • 4 Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
PMID: 39722476 DOI: 10.1021/acs.jmedchem.4c01548
Abstract

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(2H)-one derivatives were designed and synthesized. Through a systematic SAR study, D3 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 D3 was tightly interacted with PRMT5. Meanwhile, D3 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, D3 possessed excellent antitumor efficacy in Z-138 xenograft models, low toxicity in vivo, and acceptable drug metabolism and pharmacokinetics (DMPK) profiles in vitro. Therefore, D3 can be developed as a promising candidate for the treatment of non-Hodgkin's lymphoma (NHL).

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