Format

Send to

Choose Destination
J Biomol Screen. 2015 Mar;20(3):382-90. doi: 10.1177/1087057114559490. Epub 2014 Nov 13.

High-content phenotypic screening and triaging strategy to identify small molecules driving oligodendrocyte progenitor cell differentiation.

Author information

1
Lead Generation & Candidate Realization, Sanofi Tucson Innovation Center, Tucson, AZ, USA.
2
Lead Generation & Candidate Realization, Sanofi R&D, Bridgewater, NJ, USA.
3
Information Services, Genzyme, Framingham, MA, USA.
4
MS and Neurology Clinical, Sanofi-Genzyme, Bridgewater, NJ, USA Karen.chandross@sanofi.com.

Abstract

Multiple Sclerosis is a demyelinating disease of the CNS and the primary cause of neurological disability in young adults. Loss of myelinating oligodendrocytes leads to neuronal dysfunction and death and is an important contributing factor to this disease. Endogenous oligodendrocyte precursor cells (OPCs), which on differentiation are responsible for replacing myelin, are present in the adult CNS. As such, therapeutic agents that can stimulate OPCs to differentiate and remyelinate demyelinated axons under pathologic conditions may improve neuronal function and clinical outcome. We describe the details of an automated, cell-based, morphometric-based, high-content screen that is used to identify small molecules eliciting the differentiation of OPCs after 3 days. Primary screening was performed using rat CG-4 cells maintained in culture conditions that normally support a progenitor cell-like state. From a library of 73,000 diverse small molecules within the Sanofi collection, 342 compounds were identified that increased OPC morphological complexity as an indicator of oligodendrocyte maturation. Subsequent to the primary high-content screen, a suite of cellular assays was established that identified 22 nontoxic compounds that selectively stimulated primary rat OPCs but not C2C12 muscle cell differentiation. This rigorous triaging yielded several chemical series for further expansion and bio- or cheminformatics studies, and their compelling biological activity merits further investigation.

KEYWORDS:

CNS repair; Multiple Sclerosis (MS); high-content screening (HCS); oligodendrocyte progenitor cell (OPC); phenotypic screening; remyelination

PMID:
25394729
DOI:
10.1177/1087057114559490
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center