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

International audienceThe 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 mechanismbased 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 activitybased probes

IDENTIFICATION OF FIRST-IN-CLASS INHIBITORS OF KALLIKREIN-RELATED PEPTIDASE 6 THAT PROMOTE OLIGODENDROCYTE DIFFERENTIATION

International audienceMultiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that causes severe motor, sensory and cognitive impairments. KLK6 is the most abundant serine protease secreted in the CNS, mainly by oligodendrocytes, the myelinproducing 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 KLK6 proteolytic network encompassing KLK1 and plasmin that also participate to the development of MS physiopathology. Moreover, hits were found non-cytotoxic on primary cultures of murine neurons and oligodendrocyte precursors (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