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

Guolin Wu, Haixia Wang, Wenhui Zhou, Bihua Zeng, Wenhui Mo, Kejie Zhu, Rong Liu, Jia Zhou, Ceshi Chen, Haijun Chen

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3321-3344
Number of pages24
JournalBioorganic and Medicinal Chemistry
Issue number12
StatePublished - Jul 23 2018


  • Cancer therapeutics
  • MALT1
  • MI-2 analogues
  • Structure–activity relationships

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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