Identification of First-in-Class Inhibitors of Kallikrein-Related Peptidase 6 That Promote Oligodendrocyte Differentiation

J Med Chem. 2021 May 13;64(9):5667-5688. doi: 10.1021/acs.jmedchem.0c02175. Epub 2021 May 5.


Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that causes severe motor, sensory, and cognitive impairments. Kallikrein-related peptidase (KLK)6 is the most abundant serine protease secreted in the CNS, mainly by oligodendrocytes, the myelin-producing cells of the CNS, and KLK6 is assumed to be a robust biomarker of MS, since it is highly increased in the cerebrospinal fluid (CSF) of MS patients. Here, we report the design and biological evaluation of KLK6's low-molecular-weight inhibitors, para-aminobenzyl derivatives. Interestingly, selected hit compounds were selective of the KLK6 proteolytic network encompassing KLK1 and plasmin that also participate in the development of MS physiopathology. Moreover, hits were found noncytotoxic on primary cultures of murine neurons and oligodendrocyte precursor cells (OPCs). Among them, two compounds (32 and 42) were shown to promote the differentiation of OPCs into mature oligodendrocytes in vitro constituting thus emerging leads for the development of regenerative therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzene Derivatives / chemistry
  • Benzene Derivatives / metabolism
  • Benzene Derivatives / pharmacology
  • Binding Sites
  • Catalytic Domain
  • Cell Differentiation / drug effects*
  • Cells, Cultured
  • Drug Design
  • Fibrinolysin / antagonists & inhibitors
  • Fibrinolysin / metabolism
  • Humans
  • Kallikreins / antagonists & inhibitors*
  • Kallikreins / metabolism
  • Kinetics
  • Mice
  • Molecular Docking Simulation
  • Multiple Sclerosis / metabolism
  • Multiple Sclerosis / pathology
  • Neurons / cytology
  • Neurons / metabolism
  • Oligodendroglia / cytology
  • Oligodendroglia / metabolism
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / metabolism
  • Serine Proteinase Inhibitors / pharmacology*
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Structure-Activity Relationship


  • Benzene Derivatives
  • Serine Proteinase Inhibitors
  • KLK6 protein, human
  • Kallikreins
  • Fibrinolysin