2. Academic Validation
  3. Synthesis and structure-activity relationship studies of MI-2 analogues as MALT1 inhibitors

Synthesis and structure-activity relationship studies of MI-2 analogues as MALT1 inhibitors

  • Bioorg Med Chem. 2018 Jul 23;26(12):3321-3344. doi: 10.1016/j.bmc.2018.04.059.
Guolin Wu 1,  Haixia Wang 2,  Wenhui Zhou 3,  Bihua Zeng 1,  Wenhui Mo 1,  Kejie Zhu 1,  Rong Liu 4,  Jia Zhou 5,  Ceshi Chen 6,  Haijun Chen 7
Affiliations

Affiliations

  • 1 College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China.
  • 2 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology Kunming, Yunnan 650223, China; University of Science and Technology of China, Hefei, Anhui 230027, China.
  • 3 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology Kunming, Yunnan 650223, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Biomedical Research Institute, Hubei University of Medicine, Shiyan, Hubei 442000, China.
  • 4 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology Kunming, Yunnan 650223, China.
  • 5 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • 6 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology Kunming, Yunnan 650223, China. Electronic address: chenc@mail.kiz.ac.cn.
  • 7 College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China. Electronic address: chenhaij@gmail.com.
PMID: 29751989 DOI: 10.1016/j.bmc.2018.04.059
Abstract

Recent studies revealed that MALT1 is a promising therapeutic target for the treatment of ABC-DLBCL. Among several reported MALT1 inhibitors, MI-2 as an irreversible inhibitor represents a new class of ABC-DLBCL therapeutics. Due to its inherent potential cross-reactivity, further structure-activity relationship (SAR) study is imperative. In this work, five focused compound libraries based on the chemical structure of MI-2 are designed and synthesized. The systematic SARs revealed that the side chain of 2-methoxyethoxy has little impact on the activity and can be replaced by Other functionalized groups, providing new MI-2 analogues with retained or enhanced potency. Compounds 81-83 with terminal hydroxyl group as side chain displayed enhanced activities against MALT1. Replacement of triazole core with pyrazole is also tolerant, while structural modifications on Other sites are detrimental. These findings will facilitate further development of small-molecule MALT1 inhibitors.

Keywords

Cancer therapeutics; MALT1; MI-2 analogues; Structure–activity relationships.

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