Human Adipocyte Platform for Discovery of Novel Adiponectin Secretagogues

描述（由申请人提供）：Small business concerns，DiscoveryBioMed，Inc. (DBM)和Chromadex，Inc.（CDex）设计了一个创新的自动化友好的药物发现计划，以筛选药用植物来源的植物化学物质，并在永生化的人类脂肪细胞平台上提取馏分，以发现脂联素的新型选择性促分泌素，脂联素是肥胖相关疾病的既定生物标志物和致病介质。肥胖和肥胖相关疾病，包括2型糖尿病和动脉粥样硬化，在美国和发达国家已经达到流行病的比例，并对社会造成巨大的发病率和成本负担。因此，对对抗这些疾病的新药存在巨大的未满足的需求。代谢疾病的药物管道正在经历问题，许多肥胖相关疾病的“新药”只是重新命名或组合药物，具有不确定的减肥副作用。肥胖和糖尿病患者体内脂肪因子脂联素的血浆浓度降低。此外，降低的循环脂联素是公认的代谢性疾病的生物标志物和病原体。因此，上调脂联素表达已被提出作为肥胖相关疾病的高优先级治疗策略。这一由SBIR驱动的第一阶段合作伙伴关系和计划将把这两家小型企业的最大优势整合到一个高度创新的药物发现平台中：DBM提供的生理相关永生化人类内脏脂肪细胞平台和基于细胞的靶向和表型筛选方法，以及CDex提供的药用植物提取物馏分、植物化学物质和植物化学衍生物/类似物的筛选库。DBM将首先分化来自内脏贮库部位的永生化人前脂肪细胞。成熟的脂肪细胞将与CDex的药用植物衍生的化合物库的挑战，发现新的脂联素促分泌素。在整个过程中，我们将采用精心设计的关键路径，包括一级、二级和三级发现和验证步骤，以识别“高价值”的先导化合物。DBM提出了以下里程碑，并将显示迄今为止取得的进展：（1）设计和优化自动化友好的永生化的“汇集供体”人内脏脂肪细胞为基础的药物发现平台，以检测分泌的脂联素;（2）利用CDex的10，000 - 12，000种药用植物提取物馏分、纯化的植物化学物质、和植物化学类似物/衍生物，以发现和验证新的选择性脂联素促分泌素;和（3）开始建立基于先导化合物、结构相似化合物和药物化学衍生物的连续非定向（随机）筛选和定向（靶向）筛选的平行轨道。该计划的最终目标是发现命中领先的植物化学物质和植物化学类似物，这些植物化学物质和植物化学类似物可以显著增强分化脂肪细胞中的内源性（天然）脂联素分泌，这些脂联素可以开发成未来的药物，以减缓全球肥胖和糖尿病的发展。 公共卫生相关性：肥胖症、糖尿病和相关的代谢紊乱是流行病，有成为大流行病的危险。越来越不健康的饮食和久坐不动的生活方式相结合，导致截至2010年全世界20亿成年人和数百万儿童超重或肥胖。未来的人类健康负担是巨大的，可能是灾难性的。到2015年，美国和世界的成本估计将超过1万亿美元。当发现生物医学公司和Chromadex，Inc.在我们建立合作伙伴关系时，我们最初和第一个目标市场或焦点是肥胖症和糖尿病。我们寻求联合收割机，协同努力，发现新的药物，阻止这一令人震惊的潮流，减轻这些深刻的代谢疾病。对于DBM来说，这是一个地方性的使命，考虑到亚拉巴马和我们地区危险的肥胖和糖尿病趋势。

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 are experiencing 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 human visceral 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 will first 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 will apply 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 and diabetes. 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 Alabama and in our region.