2. Academic Validation
  3. Design, synthesis and biological evaluation of sulfonamides inhibitors of XPO1 displaying activity against multiple myeloma cells

Design, synthesis and biological evaluation of sulfonamides inhibitors of XPO1 displaying activity against multiple myeloma cells

  • Eur J Med Chem. 2022 May 5;235:114257. doi: 10.1016/j.ejmech.2022.114257.
Bingxue Qu 1,  Yongjin Xu 2,  Yang Lu 3,  Weihao Zhuang 3,  Xinxin Jin 3,  Qiuqiu Shi 3,  Shike Yan 3,  Yu Guo 3,  Zheyuan Shen 4,  Jinxin Che 5,  Yize Wu 3,  Lexian Tong 4,  Xiaowu Dong 6,  Haiyan Yang 7
Affiliations

Affiliations

  • 1 Department of Lymphoma, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, PR China; Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
  • 2 Department of Lymphoma, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, PR China.
  • 3 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
  • 4 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, PR China.
  • 5 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, PR China.
  • 6 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, PR China; Cancer Center, Zhejiang University, Hangzhou, PR China. Electronic address: dongxw@zju.edu.cn.
  • 7 Department of Lymphoma, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, PR China. Electronic address: yanghy@zjcc.org.cn.
PMID: 35367710 DOI: 10.1016/j.ejmech.2022.114257
Abstract

Multiple myeloma (MM) is a highly malignant hematologic Cancer that occurs when an atypical plasma cell develops in the bone marrow and reproduces quickly. Despite varies of new drugs have been developed or under clinic trial, MM is still essentially incurable, while XPO1 inhibition has emerged as a promising therapeutic strategy in the treatment of MM. Using the second-generation XPO1 inhibitor KPT-8602 as the lead compound, structure-based optimization provided D4 with high anti-proliferation efficacy (IC50 = 24 nM in MM.1S). In addition, the treatment with D4 significantly induced MM.1S cell cycle arrested and cell Apoptosis, which was confirmed as on-target effect by immunofluorescence microscopy and competitive binding assay. Moreover, D4 displayed good metabolic stability over rat plasma and liver microsomes, as well as good pharmacokinetic profile on SD rat model with high drug exposure and decent bioavailability by oral gavage. All these good properties of D4 pave the way for further drug development and clinical application.

Keywords

MM.1S; Multiple myeloma; N-phenylsulfonamide; Oral administration; XPO1.

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