Peptide-based covalent inhibitors of MALT1 paracaspase

John M. Hatcher, Guangyan Du, Lorena Fontán, Ilkay Us, Qi Qiao, Spandan Chennamadhavuni, Jay Shao, Hao Wu, Ari Melnick, Nathanael S. Gray, David A. Scott

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Potent and selective substrate-based covalent inhibitors of MALT1 protease were developed from the tetrapeptide tool compound Z-VRPR-fmk. To improve cell permeability, we replaced one arginine residue. We further optimized a series of tripeptides and identified compounds that were potent in both a GloSensor reporter assay measuring cellular MALT1 protease activity, and an OCI-Ly3 cell proliferation assay. Example compounds showed good overall selectivity towards cysteine proteases, and one compound was selected for further profiling in ABL-DLBCL cells and xenograft efficacy models.

Original languageEnglish (US)
Pages (from-to)1336-1339
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number11
DOIs
StatePublished - Jun 1 2019
Externally publishedYes

Keywords

  • Covalent
  • Inhibitors
  • Peptide
  • Protease

ASJC Scopus subject areas

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

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