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Innovative screening strategy swiftly uncovers new drug candidates, new biology
Date:12/22/2013

t-based screening has enabled scientists to discover many useful new drugs, but some wonder whether this basic discovery strategy has already taken all the "low hanging fruit." In recent years, compounds selected with target-based in vitro tests have seemed to be failing increasingly often when tested in the more realistic biological environments of cells and animals.

An older strategy, "phenotypic" screening, avoids much of this problem by testing compounds for their ability to produce a desired effect directly on living cells. Unfortunately, such cell-based tests often leave open the question of how a useful compound works. "If you don't know what its relevant molecular target is, then developing that compound into a drugoptimizing its potency, its selectivity, its half-life in the bloodstream and so onis going to be difficult," said Saez.

Identifying the molecular targets of compounds selected by phenotypic screens is typically burdensome and time-consuming. But in their new study, Saez, Cravatt and their colleagues were able to speed up the process dramatically. Indeed, their combined phenotypic screening and target-identification approach enabled them to quickly discover, characterize and carry out preclinical tests of a potential new drug for obesity-linked diabetes: a complex metabolic disorder that affects 347 million people worldwide.

A New Diabetes Drug Candidate, Plus Insights into the Disease

The strategy makes use of the increasing availability of special libraries of related compounds that act as inhibitors of entire enzyme classes. In this case, the researchers used a set of compounds, recently synthesized by Cravatt's laboratory, that tend to inhibit serine hydrolasesa vast enzyme family whose members participate in most biological processes in mammals.

The scientists started with a phenotypic screen, testing their library of compounds for the ability to make young fat cells mature faster and store more
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Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute
Source:Eurekalert  

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