| Literature DB >> 30773481 |
Dharmaraja Allimuthu1, Zita Hubler1, Fadi J Najm1, Hong Tang2, Ilya Bederman3, William Seibel4, Paul J Tesar1, Drew J Adams5.
Abstract
Small molecules that promote oligodendrocyte formation have been identified in "drug repurposing" screens to nominate candidate therapeutics for diseases in which myelin is lost, including multiple sclerosis. We recently reported that many such molecules enhance oligodendrocyte formation not by their canonical targets but by inhibiting a narrow range of enzymes in cholesterol biosynthesis. Here we identify enhancers of oligodendrocyte formation obtained by screening a structurally diverse library of 10,000 small molecules. Identification of the cellular targets of these validated hits revealed a majority inhibited the cholesterol biosynthesis enzymes CYP51, TM7SF2, or EBP. In addition, evaluation of analogs led to identification of CW3388, a potent EBP-inhibiting enhancer of oligodendrocyte formation poised for further optimization.Entities:
Keywords: cholesterol; glial biology; high-content imaging; multiple sclerosis; oligodendrocyte; phenotypic screening; remyelination; sterol signaling; target identification
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Year: 2019 PMID： 30773481 PMCID： PMC6474808 DOI： 10.1016/j.chembiol.2019.01.004
Source DB: PubMed Journal: Cell Chem Biol ISSN： 2451-9448 Impact factor: 8.116