Repurposing HAMI3379 to Block GPR17 and Promote Rodent and Human Oligodendrocyte Differentiation. Issue 6 (21st June 2018)

• Record Type: Journal Article
• Authors: Merten, Nicole; Fischer, Julia; Simon, Katharina; Zhang, Liguo; Schröder, Ralf; Peters, Lucas; Letombe, Anne-Gaelle; Hennen, Stephanie; Schrage, Ramona; Bödefeld, Theresa; Vermeiren, Celine; Gillard, Michel; Mohr, Klaus; Lu, Qing Richard; Brüstle, Oliver; Gomeza, Jesus; Kostenis, Evi
• Is Part Of: Cell chemical biology. Volume 25:Issue 6(2018)
• Page Start: 775
• Page End: 786.e5
• Publication Date: 2018-06-21
• Subjects: G protein-coupled receptor -- GPCR -- GPR17 -- orphan GPCR -- HAMI3379 -- oligodendrocyte -- demyelinating disease -- drug repurposing -- signal transduction -- label-free dynamic mass redistribution; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.03.012
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Identification of additional uses for existing drugs is a hot topic in drug discovery and a viable alternative to de novo drug development. HAMI3379 is known as an antagonist of the cysteinyl-leukotriene CysLT2 receptor, and was initially developed to treat cardiovascular and inflammatory disorders. In our study we identified HAMI3379 as an antagonist of the orphan G protein-coupled receptor GPR17. HAMI3379 inhibits signaling of recombinant human, rat, and mouse GPR17 across various cellular backgrounds, and of endogenous GPR17 in primary rodent oligodendrocytes. GPR17 blockade by HAMI3379 enhanced maturation of primary rat and mouse oligodendrocytes, but was without effect in oligodendrocytes from GPR17 knockout mice. In human oligodendrocytes prepared from inducible pluripotent stem cells, GPR17 is expressed and its activation impaired oligodendrocyte differentiation. HAMI3379, conversely, efficiently favored human oligodendrocyte differentiation. We propose that HAMI3379 holds promise for pharmacological exploitation of orphan GPR17 to enhance regenerative strategies for the promotion of remyelination in patients. Graphical Abstract: Highlights: Experimental drug HAMI3379 repurposed as inhibitor of orphan GPR17 HAMI3379 favors differentiation of rodent and human oligodendrocytes in culture Pro-differentiation effects of HAMI3379 are mediated by GPR17 Alternative-application discovery for HAMI3379 as strategy to treat demyelinating diseases Abstract : Identification of alternative uses for existing drugs is a hot topic in drug discovery. Merten et al. repurposed the experimental drug HAMI3379, originally developed to treat cardiovascular and inflammatory disorders, for pharmacological exploitation of orphan GPR17, and thereby enhance regenerative strategies for promotion of remyelination in patients.