Adipokine Secretion Enhancer Synthetic Organic Drug Discovery in Human Adipocytes

人类脂肪细胞中脂肪因子分泌增强剂合成有机药物的发现

• 批准号: 8590766
• 负责人: ERIC CLINTON SEALES
• 金额: $ 22.47万
• 依托单位: DISCOVERYBIOMED, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2014-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8590766
• 关键词: Abdomen; Adipocytes; Adult; Adverse effects; Affect; Alabama; Atherosclerosis; Automation; Biochemistry; Biological Assay; Biological Markers; Body Weight decreased; Cardiovascular Diseases; Cells; Chemicals; Child; Clinical; Collection; Complex; Computers; Coupled; Critical Pathways; Data; Diabetes Mellitus; Diet; Disease; Eating; Enhancers; Enzyme-Linked Immunosorbent Assay; Epidemic; Eye; Eye Injuries; Fatty Liver; Funding; Future; Goals; Health; Heart; Housing; Human; Hyperglycemia; Incidence; Industry; Injury; Insulin; Kidney; Kindling (Neurology); Lead; Legal patent; Life Style; Liver diseases; Marketing; Mediator of activation protein; Metabolic Diseases; Methods; Molecular Bank; Morbidity - disease rate; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Organ; Output; Overweight; Patients; Peripheral Nerves; Pharmaceutical Preparations; Phase; Plasma; Process; Regimen; Research; Resources; Risk; Series; Small Business Innovation Research Grant; Social Network; Societies; Testing; Therapeutic; Tissues; Validation; Video Games; Visceral; Vision; Work; adiponectin; base; combat; cost; design; diabetic; diabetic patient; disorder control; drug candidate; drug discovery; fast food; glucagon-like peptide; glycosylation; in vivo; indexing; innovation; medical specialties; novel; novel therapeutics; pandemic disease; programs; public health relevance; screening; sedentary; small molecule

DESCRIPTION (provided by applicant): DiscoveryBioMed, Inc. (DBM) has launched an innovative and automation-friendly drug discovery program to screen synthetic organic small molecule collections on differentiated human adipocyte platforms to discover a new class of therapeutic drugs for type 2 diabetes mellitus (T2DM) and obesity. Differentiated human adipocytes from visceral (central abdominal depot) origin are challenged with test compounds to discover hit small molecules that trigger the secretion of endogenous adiponectin. Adiponectin is an established biomarker and causative mediator in obesity-related diseases. Plasma concentrations of this adipokine are reduced in vivo in obese and diabetic patients. Accordingly, up-regulating endogenous adiponectin expression and secretion has been proposed as a high-priority therapeutic strategy for obesity-related diseases. The ultimate goal of this work is to develop, optimize, validate and implement the human fat cell-driven drug discovery platform based on immortalized and primary human visceral adipocytes to discover novel adiponectin secretagogues for obesity, diabetes and related metabolic diseases as well as ailments that arise from secondary complications of metabolic disease. The key ingredient in this program is DBM's core principle of using biologically- and disease-relevant human cellular platforms to 'de-risk' de novo drug discovery programs. This core principle reflects DBM's unique angle, approach and offering to the drug discovery space. Primary and immortal human pre-adipocytes from normal donors and type 2 diabetes mellitus patients are differentiated by a patent-protected process that employs a novel differentiation medium. It is DBM's view that successful de novo drug discovery programs must utilize a disease-relevant human cell platform and a disease-relevant target/phenotypic endpoint (i.e. human adipocytes secreting human adiponectin). Obesity and obesity-related diseases including T2DM, atherosclerosis, cardiovascular disease, fatty liver disease, and diabetic hyperglycemic injury of the eye, heart, kidney and peripheral nerves have reached epidemic proportions in the US and the developed world and exact huge morbidity and cost burdens on society. An enormous unmet clinical need exists for new therapeutic drugs to combat these diseases, especially in Alabama where DBM resides in the heart of "the Southeastern Diabetes Belt." Drug pipelines for metabolic diseases are in peril, with most pipeline drugs for obesity-related diseases simply re-branded, re-purposed or combined because of an undefined weight loss side effect. Many of these new or re-purposed drug classes for metabolic diseases have failed and been abandoned recently. There is dire need and window of opportunity to re-kindle the metabolic diseases drug discovery effort with novel and innovative programs. DBM rises to that unmet need with the following major project milestones that: (1) Establish a robust differentiated human visceral adipocyte drug discovery platform; (2) Design, optimize and implement a primary de novo drug discovery HTS-friendly bioassay; (3) Screen the 60,000 synthetic organic compounds within the DBM molecular library to discover novel endogenous adiponectin secretagogues; (4) Validate putative hits from the primary HTS bioassay with a robust Critical Path; and (5) Perform chemoinformatics on the validated hit compounds to identify hit-to-lead chemical classes worthy of deeper assessment and profiling. DBM is already 10% of the way to this screening goal and has already performed validation and chemoinformatics on the early output from our Critical Path. DBM seeks SBIR funds to deepen and accelerate this critical metabolic diseases drug discovery program.

描述（由申请人提供）：DiscoveryBioMed，Inc. (DBM)该公司推出了一项创新和自动化友好的药物发现计划，在分化的人类脂肪细胞平台上筛选合成有机小分子集合，以发现一类新的2型糖尿病（T2DM）和肥胖症治疗药物。用测试化合物激发来自内脏（中央腹部贮库）来源的分化的人脂肪细胞，以发现触发内源性脂联素分泌的命中小分子。脂联素是肥胖相关疾病的既定生物标志物和致病介质。这种脂肪因子的血浆浓度在肥胖和糖尿病患者体内降低。因此，上调内源性脂联素的表达和分泌已被提出作为肥胖相关疾病的高优先级治疗策略。这项工作的最终目标是开发，优化，验证和实施基于永生化和原代人类内脏脂肪细胞的人类脂肪细胞驱动的药物发现平台，以发现用于肥胖，糖尿病和相关代谢疾病以及由代谢疾病继发性并发症引起的疾病的新型脂联素促分泌素。该计划的关键要素是DBM的核心原则，即使用生物学和疾病相关的人类细胞平台来“降低”从头药物发现计划的风险。这一核心原则反映了DBM对药物发现空间的独特视角、方法和贡献。来自正常供体和2型糖尿病患者的原代和永生人类前脂肪细胞通过专利保护的方法分化，该方法采用新型分化培养基。DBM认为，成功的从头药物发现计划必须利用疾病相关的人类细胞平台和疾病相关的靶点/表型终点（即分泌人脂联素的人脂肪细胞）。肥胖和肥胖相关疾病，包括T2DM、动脉粥样硬化、心血管疾病、脂肪肝疾病和糖尿病性高血糖对眼睛、心脏、肾脏和周围神经的损伤，在美国和发达国家已达到流行病的程度，并给社会带来巨大的发病率和成本负担。一个巨大的未满足的临床需要存在的新的治疗药物，以打击这些疾病，特别是在亚拉巴马，其中DBM居住在心脏的"东南糖尿病带。“用于代谢疾病的药物管道处于危险之中，大多数用于肥胖相关疾病的管道药物只是因为不确定的减肥副作用而重新命名，重新使用或合并。许多这些新的或重新用于代谢疾病的药物类别最近已经失败并被放弃。迫切需要和机会之窗重新点燃代谢疾病药物发现的努力与新颖和创新的计划。DBM通过以下主要项目里程碑来满足这一未满足的需求：（1）建立一个强大的分化的人类内脏脂肪细胞药物发现平台;（2）设计、优化和实施一个初步的从头药物发现HTS友好的生物测定;（3）筛选DBM分子库中的60，000种合成有机化合物，以发现新的内源性脂联素促分泌素;（4）用稳健的关键路径从初级HTS生物测定中推断命中;和（5）对经验证的命中化合物进行化学信息学，以鉴定值得更深入评估和分析的命中先导化合物类别。DBM已经完成了这一筛选目标的10%，并且已经对我们的关键路径的早期输出进行了验证和化学信息学。DBM寻求SBIR资金来深化和加速这一关键代谢疾病药物发现计划。