Human Adipocyte Platform for Discovery of Novel Adiponectin Secretagogues

DESCRIPTION (provided by applicant): Small business concerns, DiscoveryBioMed, Inc. (DBM) and Chromadex, Inc. (CDex), have designed an innovative automation-friendly drug discovery program to screen medicinal plant-derived phytochemicals and extract fractions on an immortalized human adipocyte platform to discover novel, selective secretagogues of adiponectin, an established biomarker and causative mediator in obesity-related diseases. Obesity and obesity-related diseases including Type 2 diabetes and atherosclerosis have reached epidemic proportions in the US and the developed world and are causing huge morbidity and cost burdens on society. As such, there is a huge, unmet need for new drugs to combat these diseases. Drug pipelines in metabolic diseases areexperiencing problems, and many new drugs for obesity-related diseases are simply re-branded or combined pharmaceuticals with an undefined weight loss side effect. Plasma concentrations of the adipokine, adiponectin, are reduced in vivo in obese and diabetic patients. Furthermore, reduced circulating adiponectin is well-established as both a biomarker of and a causative agent in metabolic diseases. Accordingly, up-regulating adiponectin expression has been proposed as a high-priority therapeutic strategy for obesity-related diseases. This Phase 1 SBIR-driven partnership and program will integrate the greatest strengths of these two small business concerns into one highly innovative drug discovery platform: the physiologically-relevant immortalized humanvisceral adipocyte platform and cell-based targeted and phenotypic screening methodology provided by DBM and a screening library of medicinal plant-derived extract fractions, phytochemicals, and phytochemical derivatives/analogs provided by CDex. DBM willfirst differentiate immortalized human preadipocytes derived from visceral depot sites. Mature adipocytes will be challenged with CDex s medicinal plant-derived compound library to discover novel adiponectin secretagogues. Throughout the process, we willapply a carefully designed Critical Path of primary, secondary and tertiary discovery and validation steps to identify high value hit-to-lead compounds. DBM proposes the following milestones and will show progress achieved to date: (1) Design and optimize an automation- friendly immortalized 'pooled donor' human visceral adipocyte-based drug discovery platform to detect secreted adiponectin; (2) Screen our platform with CDex's diverse collection of 10,000-12,000 medicinal plant-derived botanical extract fractions, purified phytochemicals, and phytochemical analogs/derivatives to discover and validate novel selective adiponectin secretagogues; and (3) Begin to establish parallel tracks of continued non-directed (random) screening and directed (targeted)screening based on lead compounds, structurally-similar compounds and medicinal chemistry derivatives. The ultimate goal of this proposed program is to discover hit-to-lead phytochemicals and phytochemical analogs that acutely enhance endogenous (natural)adiponectin secretion in differentiated adipocytes that can be developed into future drugs to slow the development of obesity and diabetes worldwide. PUBLIC HEALTH RELEVANCE: Obesity, diabetes and related metabolic disorders are epidemics in danger of becoming pandemics. The combination of increasingly unhealthy diets and a sedentary lifestyle have contributed significantly to cause 2 billion adults and millions of children worldwide to be overweight or obese as of 2010. The future human health burden is immense and potentially catastrophic. The cost for the US and the world is estimated to exceed 1 trillion by 2015. When DiscoveryBioMed, Inc. and Chromadex, Inc. formed our partnership, our initial and first target markets or foci were obesity anddiabetes. We seek to combine our talents in a synergized effort to discover new drugs that stem this alarming tide and attenuate these profound metabolic diseases. For DBM, this is a local mission, given the dangerous obesity and diabetes trends in Alabamaand in our region.