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Cell Chem Biol. 2017 May 18;24(5):624-634.e3. doi: 10.1016/j.chembiol.2017.03.016. Epub 2017 Apr 20.

Molecular Phenotyping Combines Molecular Information, Biological Relevance, and Patient Data to Improve Productivity of Early Drug Discovery.

Author information

1
Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
2
Cellular Dynamics International, 525 Science Drive, Madison, WI 53711, USA.
3
Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. Electronic address: martin.ebeling@roche.com.
4
Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. Electronic address: marco.prunotto@roche.com.

Abstract

Today, novel therapeutics are identified in an environment which is intrinsically different from the clinical context in which they are ultimately evaluated. Using molecular phenotyping and an in vitro model of diabetic cardiomyopathy, we show that by quantifying pathway reporter gene expression, molecular phenotyping can cluster compounds based on pathway profiles and dissect associations between pathway activities and disease phenotypes simultaneously. Molecular phenotyping was applicable to compounds with a range of binding specificities and triaged false positives derived from high-content screening assays. The technique identified a class of calcium-signaling modulators that can reverse disease-regulated pathways and phenotypes, which was validated by structurally distinct compounds of relevant classes. Our results advocate for application of molecular phenotyping in early drug discovery, promoting biological relevance as a key selection criterion early in the drug development cascade.

KEYWORDS:

calcium signaling; cardiomyocytes; drug discovery; high-throughput RNA sequencing; molecular phenotypic screening; pathway reporters

PMID:
28434878
DOI:
10.1016/j.chembiol.2017.03.016
[Indexed for MEDLINE]
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