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
  • 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: [email protected].
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.