Navigation Links
Innovative screening strategy swiftly uncovers new drug candidates, new biology

LA JOLLA, CADecember 22, 2013Scientists at The Scripps Research Institute (TSRI) have demonstrated a drug-discovery strategy with a double payoffit enables the rapid selection of chemical compounds that have a desired effect on cells and also highlights how the compounds work.

To illustrate the power of the innovative technique, the TSRI researchers used it to identify a compound that shows promise for treating obesity-linked diabetes. At the same time, they were able to identify the fat-cell enzyme that the compound inhibitsan enzyme that has not yet been a focus of diabetes drug development.

"This integrated strategy we've developed has the potential to accelerate the discovery of important biological pathways and may lead to faster development of new drugs for multiple diseases," said TSRI Associate Professor Enrique Saez.

Saez and his colleague Benjamin F. Cravatt, chair of TSRI's Department of Chemical Physiology, were the senior authors of the new study, which is reported December 22, 2013, in an advance online issue of Nature Chemical Biology.

Facilitating Drug Discovery

The new strategy has great potential to streamline drug discovery, a process whose importance to human health can hardly be overemphasized.

Typically, pharmaceutical scientists start the discovery process by "screening" large libraries of chemical compounds in search of one or a few that might treat disease. The dominant strategy of recent decades has been to screen compounds for a specific activity against a known target, for example, inhibiting the function of a certain enzyme thought to be critical for the disease in question. A key advantage of this "target-based" screening is that it uses biochemical tests that can be done relatively simply in a test-tubeor rather, in a large array of tiny test tubes via automated, rapid screening systems that sort through hundreds of thousands of different compounds.

Target-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 fat. Better fat storage means that less fat leaks from fat cells into the liver, muscles and pancreasa process that frequently occurs with obesity, often interfering with insulin signaling enough to bring on diabetes.

The screen quickly yielded several compounds that had a strong effect in promoting fat-cell fat storage. The researchers then used a method called "activity-based profiling" to identify the fat-cell serine hydrolases that the compounds inhibited most strongly. One of the most potent compounds, WWL113, turned out to work principally by inhibiting Ces3, a serine hydrolase enzyme that scientists have not studied in the context of obesity or diabetes.

The researchers quickly demonstrated WWL113's effectiveness in two different mouse models of obesity-linked diabetesone in which the mice are genetically programmed to become obese and diabetic, and another in which normal mice are made obese and diabetic with a high-fat diet. "The treated animals showed resistance to weight gainthey were not putting on as much weight as the controls," said Saez. "Their blood biochemistry also was getting normalized; their glucose, triglyceride and cholesterol levels were coming down towards normal levels."

In these mouse tests, WWL113without any optimization for use as a drugperformed about as well as the FDA-approved diabetes treatment rosiglitazone (Avandia). Notably, the new compound lacked one of the side effects that drugs in rosiglitazone's class have in mice: the toxic accumulation of lipids in the liver.

"Our compound clears lipids from the diabetic mouse liver, whereas rosiglitazone has the opposite effect," said Saez.

To explore the relevance of these results to humans, the TSRI team worked with collaborating researchers in Australia to test fat samples from obese humans and diabetics. The tests confirmed that the human version of Ces3 also is unusually active in such patients. This suggests that an inhibitor may also work as a diabetes treatment in people.

Saez and his colleagues will next focus on using the new screening strategy to uncover more biological pathways that could yield new mechanisms to develop potential therapies.


Contact: Mika Ono
Scripps Research Institute

Related biology news :

1. Innovative drug-dispensing contact lens delivers glaucoma medication continuously for a month
2. Bruin Biometrics, LLC Awarded CE Mark for the SEM Scanner, an Innovative Diagnostic Tool to Detect Pressure Induced Tissue Damage
3. Chair Mats of Glass Company Clearly Innovative Announces the Launch of 20 New Dealers in the Midwest
4. Innovative MIT study estimates extent to which air pollution in China shortens human lives
5. AAOS awards recognize innovative orthopaedic research
6. Unlikely partners create innovative product for college biology
7. International space station plays host to innovative infectious disease research
8. Innovative uses of nanotechnology in food and agriculture
9. Mussels inspire innovative new adhesive for surgery
10. MVI and Inovio partner to develop malaria vaccines using innovative vaccine delivery tech
11. NIH awards Penn scientists $10 million over 5 years for innovative research on single cells
Post Your Comments:
Related Image:
Innovative screening strategy swiftly uncovers new drug candidates, new biology
(Date:11/11/2015)... , Nov. 11, 2015   MedNet Solutions , ... spectrum of clinical research, is pleased to announce that it ... Clinical Trials (PCT) event, to be held November 17-19 ... able to view live demonstrations of iMedNet ... learn how iMedNet has been able to deliver ...
(Date:11/10/2015)... About signature verification Signature ... identify and verify the identity of an individual ... secure and accurate method of authentication and is ... because each individual,s signature is highly unique. Signature ... signature of an individual is compared and matched ...
(Date:11/9/2015)... SAN JOSE, Calif. , Nov. 9, 2015 /PRNewswire/ ... of human interface solutions, today announced broader entry into ... of vehicle-specific solutions that match the pace of consumer ... drivers, and biometric sensors are ideal for the automotive ... the vehicle. Europe , ...
Breaking Biology News(10 mins):
(Date:11/24/2015)...  Tikcro Technologies Ltd. (OTCQB: TIKRF) today announced that its Annual General ... a.m. Israel time, at the law offices of ... 36 th Floor, Tel Aviv, Israel . ... Izhak Tamir to the Board of Directors; , election ... , approval of an amendment to certain terms of options granted to ...
(Date:11/24/2015)... (PRWEB) , ... November 24, 2015 , ... ... and the environment are paramount. Insertion points for in-line sensors can represent a ... developed the InTrac 781/784 series of retractable sensor housings , which are ...
(Date:11/24/2015)... Telbec/ - ProMetic Life Sciences Inc. (TSX: PLI) (OTCQX: PFSCF) ... Laurin , President and Chief Executive Officer of ProMetic, will ... 27 th Annual Healthcare Conference to be held at ... st , at 8.50am (ET) and ProMetic,s management ... The presentation will be available live via a webcast accessible ...
(Date:11/24/2015)... INCLINE VILLAGE, Nev. , Nov. 24, 2015  PDL ... John P. McLaughlin , the company,s president and chief ... Piper Jaffray Healthcare Conference next week in New ... and will occur on Tuesday, December 1, 2015 at 9:30 ... and Presentations." Please connect to the website at least 15 ...
Breaking Biology Technology: