Insights into the activity control of the kallikrein-related peptidase 6: small-molecule modulators and allosterism

Biol Chem. 2018 Sep 25;399(9):1073-1078. doi: 10.1515/hsz-2017-0336.

Abstract

The activity of kallikrein-related peptidase 6 (KLK6) is deregulated in various diseases such as cancer and neurodegenerative diseases. KLK6 is thus considered as an attractive therapeutical target. In this short report, we depict some novel findings on the regulation of the KLK6 activity. Namely, we identified mechanism-based inhibitors (suicide substrates) from an in-house library of 6-substituted coumarin-3-carboxylate derivatives. In addition, a molecular dynamics study evidenced the allosteric behavior of KLK6 similar to that previously observed for some trypsin-like serine proteases. This allosteric behavior together with the coumarinic scaffold bring new opportunities for the design of KLK6 potent activity modulators, useful as therapeutics or activity-based probes.

Keywords: kallikrein-related peptidase 6; serine protease allostery; small-organic modulators; suicide substrate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Coumarins / chemistry
  • Coumarins / pharmacology*
  • Humans
  • Kallikreins / antagonists & inhibitors*
  • Kallikreins / metabolism
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*

Substances

  • Coumarins
  • Small Molecule Libraries
  • KLK6 protein, human
  • Kallikreins
  • coumarin-3-carboxylic acid