Diverse Chemical Scaffolds Enhance Oligodendrocyte Formation by Inhibiting CYP51, TM7SF2, or EBP

Abstract

Highlights d A small-molecule screen identified novel enhancers of oligodendrocyte formation d Most top compounds target cholesterol biosynthesis enzymes CYP51, TM7SF2, or EBP d Evaluation of analogs identified CW3388 as a potent, selective EBP inhibitor d CW3388 is poised for further optimization toward EBPtargeting remyelinating drugs

Identification of novel myelin repair drugs by modulation of oligodendroglial differentiation competence

“…We nevertheless took advantage of this potent mechanism in order to identify compounds that can modulate early oligodendroglial cell stages in contrast to the majority of other screenings which were mainly based on MBP expression and which also addressed later stages and larger time windows [ [21] , [22] , [23] , [24] , [25] , [26] , 38 , 39 , 49 , 50 ]. Moreover, the 1280 compounds tested here mainly consisted of either FDA/EMA- (US Food and Drug Administration/Europeans Medicines Agency) approved substances or substances with a clinical trial history, with 98% of them being predicted to have a high blood-brain-boundary (BBB) penetrance.…”

“…Moreover, the 1280 compounds tested here mainly consisted of either FDA/EMA- (US Food and Drug Administration/Europeans Medicines Agency) approved substances or substances with a clinical trial history, with 98% of them being predicted to have a high blood-brain-boundary (BBB) penetrance. In addition, we tested all substances using primary OPCs which creates a condition closer to the in vivo situation as compared to cell lines or stem cell derivates that were used in most related screenings [ [23] , [24] , [25] , 38 , 39 , [49] , [50] , [51] , [52] ]. Such unique selling points, however, included the backdrop of larger variations when using primary cells as well as the fact that p57kip2 translocation appears to be an early and fast process, the detection of which can be missed.…”

Electrospun Fiber Scaffolds for Engineering Glial Cell Behavior to Promote Neural Regeneration

“…Additionally, these fibrous scaffolds have been used to screen for potential therapeutics that target underlying molecular mechanisms relating to myelination in CNS disease. Using electrospun fiber model systems, various molecules have already been screened and shown to reduce OPC stress-related death, improve oligodendrocyte maturation, and reverse demyelinating processes [ 215 , 217 , 218 , 219 ]. For this reason, electrospun fibers will continue to be used as they provide a facile and reproducible myelinating assay [ 220 ].…”

Small Molecules with Big Promises for Curing Demyelinating Diseases

“…Drew Adams and colleagues next confirmed direct target engagement of EBP by CW9956, CW1143 and CW3388 in EBP enzymatic and cell-based assays for M1 muscarinic receptor, estrogen receptor, and kappa opioid receptor over other biological targets (Allimuthu et al, 2019). It was concluded that CW3388 and analogs enhance oligodendrocyte formation and subsequent remyelination through inhibiting cholesterol biosynthesis enzymes including CYP51, TM7SF2, or EBP (Figure 1B).…”

“…In this issue of Cell Chemical Biology, Drew Adams and colleagues (Allimuthu et al, 2019) reported the discovery of a group of new remyelinating compounds from a library of 10,000 structurally diverse small molecules using a high-content imaging phenotypic screening (Najm et al, 2015). The new oligodendrocyte enhancers would arguably have less side effects than these repositioned drugs originally developed for other indications against different or related targets.…”