2. Academic Validation
  3. Peptide-based covalent inhibitors of MALT1 paracaspase

Peptide-based covalent inhibitors of MALT1 paracaspase

  • Bioorg Med Chem Lett. 2019 Jun 1;29(11):1336-1339. doi: 10.1016/j.bmcl.2019.03.046.
John M Hatcher 1,  Guangyan Du 1,  Lorena Fontán 2,  Ilkay Us 2,  Qi Qiao 3,  Spandan Chennamadhavuni 1,  Jay Shao 1,  Hao Wu 3,  Ari Melnick 2,  Nathanael S Gray 1,  David A Scott 4
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Boston, MA 02115, USA.
  • 2 Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 3 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Boston, MA 02115, USA. Electronic address: davida_scott@dfci.harvard.edu.
PMID: 30954428 DOI: 10.1016/j.bmcl.2019.03.046
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.

Keywords

Covalent; Inhibitors; Peptide; Protease.

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