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Discovery Process Devised to Better Test Drug Effects

Enrique Saez

Enrique Saez (Scripps Research Institute)

Biomedical researchers at Scripps Research Institute in La Jolla, California developed a drug discovery method that combines the rapid screening of potential compounds with preclinical tests of the best prospects, and in the process identified a potential new compound to treat type 2 diabetes. The Scripps team led by chemical physiologists Enrique Saez and Benjamin Cravatt, with colleagues at Monash and Deakin universities in Australia, published their findings yesterday in the journal Nature Chemical Biology (paid subscription required).

Saez, Cravatt, and colleagues are seeking a better way to screen drug candidates that incorporates the best features of phenotypic screens testing compounds for their desired effects on cells, and target-based screens that test large numbers of compounds against potential, purified targets. Phenotypic screening, the older of the two methods, tests compounds for their desired effects on cells, but can be a time-consuming process and does not provide a better understanding of the underlying molecular processes behind its operation. Target-based screens tests, can operate quickly using automated equipment, but have recently been less successful in extending those positive results to more realistic settings, such as with lab animals.

The researchers devised a hybrid phenotypic screening strategy that tests compounds for their desired effects, but adds on preclinical tests of the proposed compound. To prove the concept, the team tested the process using small-molecule compounds with the potential to treat obesity-linked diabetes: a complex metabolic disorder.  Obesity, according to the Centers for Disease Control and Prevention, is one of the leading risk factors for diabetes.

The Cravatt lab at Scripps synthesized a set of compounds that inhibit a class of more than 200 enzymes known as serine hydrolases playing a key role in a variety of biological processes, linked to Alzheimer’s disease, infectious diseases, and type 2 diabetes. The researchers tested the library of synthesized compounds for their ability to encourage young fat cells speed up their maturity and thus store more fat. Storing more fat reduces the amount of fat that leaks into the pancreas, liver, and muscles, a phenomenon occurring with obesity that can interfere with insulin signaling to trigger diabetes.

The activity-based screens uncovered fat-cell serine hydrolases that the compounds strongly inhibited, and uncovered a potent compound they call WWL113 that worked by inhibiting an enzyme known as carboxylesterase 3 (Ces3), which was not previously investigated for its connection to the control of obesity or diabetes. The researchers then tested WWL113 in two types of lab mice, one type genetically programmed to become obese and diabetic, and normally-bred mice made obese and diabetic with a high-fat diet.

The results showed WWL113 effective with both types of mice. “The treated animals showed resistance to weight gain,” says Saez. “They were not putting on as much weight as the controls.” Saez adds that glucose, triglyceride and cholesterol levels in the mice also came down closer to normal levels.

In addition, raw WWL113 — without any formulation into a drug — performed as well as the  diabetes treatment rosiglitazone (marketed as Avandia), and without the potentially toxic accumulation of lipids in the liver, a side-effect of rosiglitazone. “Our compound clears lipids from the diabetic mouse liver,” notes Saez, “whereas rosiglitazone has the opposite effect.”

The colleagues in Australia ran tests of fat samples from humans with obesity and diabetes, and found the human version of the enzyme Ces3 also to be highly active in human cells, suggesting that a Ces3 inhibitor such as WWL113 may also work as a diabetes treatment. Saez and colleagues plan to further test the drug discovery strategy with more biological pathways.

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