Obesity is a serious medical condition affecting an estimated 40 million people and contributing to 300,000 deaths annually in the U. S. The appropriate regulation of energy intake and expenditure relies on complex hypothalamic neurocircuitry. Two key components of this system include neuropeptide melanocortin and its G-protein coupled receptor, the melanocortin receptor 4 (MC4R). Expression analysis, animal models, and extensive functional studies have indicated the direct involvement of MC4R in the regulation of food intake. Furthermore, the presence of mutations in MC4R was found in approximately 4%of severely obese patients, making it the most commonly mutated gene associated with obesity. Thus, MC4R is a valuable target for pharmaceutical industry for developing drugs treating obesity and related diseases. Aptus developed a novel, reliable and robust high-throughput screen (HTS) technology for evaluating compounds affect G-protein coupled receptors signaling through cAMP. This proprietary screen technology, while preserving the pharmacological properties of the receptors, greatly enhances the detection sensitivities, allowing the detection of compounds with any activities against a specific receptor. Since MC4R is a Gs-coupled receptor resulting in the increase in intracellular cAMP, it is well-suited for this HTS technology. To strengthen the drug discovery capability, Aptus has reached a co-development agreement with Array Biopharma, Inc (Boulder, CO). In this agreement, Aptus will gain exclusive access to Array's proprietary chemical libraries of more than 100,000 compounds for melanocortin receptors. In addition, Array will contribute to the design and synthesis of focus libraries based on initial leads from HTS, as well as to the lead optimization process. This proposal combines Aptus' novel GPCR drug screen technology and GPCR biology capabilities with Array's compounds and medicinal chemistry capabilities to identify and optimize high quality small molecule lead agonists against MC4R that can be further improved for pre-clinical development. Such compounds may result in a novel class of therapeutic agents for the treatment of obesity and its related diseases.
