Structure-activity relationship studies of 3-substituted pyrazoles as novel allosteric inhibitors of MALT1 protease

Bioorg Med Chem Lett. 2021 Jun 1:41:127996. doi: 10.1016/j.bmcl.2021.127996. Epub 2021 Mar 26.

Abstract

We report the discovery of a novel series of 1,5-bisphenylpyrazoles as potent MALT1 inhibitors. Structure-activity relationship exploration of a hit compound led to a potent MALT1 inhibitor. Compound 33 showed strong activity against MALT1 (IC50: 0.49 μM), potent cellular activity (NF-κB inhibition and inhibition of IL2 production), and high selectivity against caspase-3, -8, and -9. The results of a kinetics study suggest that compound 33 is a non-competitive inhibitor of MALT1 protein.

Keywords: Allosteric inhibitors; MALT1; Paracaspase; Structure activity relationship.

MeSH terms

  • Allosteric Regulation / drug effects
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / antagonists & inhibitors*
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / metabolism
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship

Substances

  • Cysteine Proteinase Inhibitors
  • Pyrazoles
  • MALT1 protein, human
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein