Obesity is a well-established risk factor for a number of diseases, including type 2 diabetes and coronary heart disease. Weight loss is the optimal treatment for type 2 diabetes, however current methods for reducing weight are insufficient for long-term weight loss. The mission of AdipoGenix, Inc. is to discover, develop, and license novel therapeutics that target the fat cell to treat obesity and related disorders. In this drug discovery effort, primary human cells will be studied thus removing the species differences that occur when using rodent cells. In Phase I, the yield and purity of preadipocytes obtained from human adipose tissue were increased. Conditions were optimized for culture and differentiation of preadipocytes into adipocytes, and assays were developed to measure the process. Using these assays in Phase II, synthetic and natural product libraries will be screened for inhibition of differentiation, and candidate compounds will be prioritized based on their specificity, potency and additional assay profiles. The primary screen will monitor inhibition of fatty acid uptake by preadipocytes exposed to differentiation-inducing conditions. Secondary screens will narrow candidates to those that inhibit differentiation specifically, and/or inhibit fatty acid uptake and storage and that have pharmaceutically acceptable properties. For lead candidates, characterization of the functional mechanism, target identification and structure-activity profiling will be performed. The proposed work is expected to lead to the clinical introduction of novel, effective drugs that reduce obesity.
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