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

International audience ; Multiple 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.