2. Academic Validation
  3. Design and synthesis of cantharidin derivative DCZ5418 as a TRIP13 inhibitor with anti-multiple myeloma activity in vitro and in vivo

Design and synthesis of cantharidin derivative DCZ5418 as a TRIP13 inhibitor with anti-multiple myeloma activity in vitro and in vivo

  • Bioorg Med Chem Lett. 2023 Dec 12:98:129590. doi: 10.1016/j.bmcl.2023.129590.
Sanfeng Dong 1,  Ke Hu 2,  Yulong Shi 3,  Guanli Wang 2,  Dandan Yu 4,  Yitian Zhao 5,  Hui Zhang 2,  Yingcong Wang 4,  Haiguo Sun 3,  Zhijian Xu 3,  Qi Jia 6,  Yiming Li 6,  Yingxia Li 7,  Bo Li 8,  Jumei Shi 9,  Weiliang Zhu 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
  • 2 Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
  • 3 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
  • 4 Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
  • 5 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
  • 6 Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
  • 7 School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
  • 8 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, No.38 Xue Yuan Road, Haidian District, Beijing 100191, China. Electronic address: boli@simm.ac.cn.
  • 9 Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: shijumei@tongji.edu.cn.
  • 10 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China. Electronic address: wlzhu@simm.ac.cn.
PMID: 38092072 DOI: 10.1016/j.bmcl.2023.129590
Abstract

Natural product cantharidin can inhibit multiple myeloma cell growth in vitro, while serious adverse effects limited its clinical application. Therefore, the structural modification of cantharidin is needed. Herein, inspired by the structural similarity of the aliphatic endocyclic moiety in cantharidin and TRIP13 inhibitor DCZ0415, we designed and synthesized DCZ5418 and its nineteen derivatives. The molecular docking study indicated that DCZ5418 had a similar binding mode to TRIP13 protein as DCZ0415 while with a stronger docking score. Moreover, the bioassay studies of the MM-cells viability inhibition, TRIP13 protein binding affinity and Enzyme inhibiting activity showed that DCZ5418 had good anti-MM activity in vitro and definite interaction with TRIP13 protein. The acute toxicity test of DCZ5418 showed less toxicity in vivo than cantharidin. Furthermore, DCZ5418 showed good anti-MM effects in vivo with a lower dose administration than DCZ0415 (15 mg/kg vs 25 mg/kg) on the tumor xenograft models. Thus, we obtained a new TRIP13 inhibitor DCZ5418 with improved safety and good activity in vivo, which provides a new example of lead optimization by using the structural fragments of Natural Products.

Keywords

Cantharidin; DCZ0415; DCZ5418; Multiple myeloma; TRIP13 inhibitor.

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