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）推出了一种创新且适合自动化的药物发现计划，以筛选差异化的人类脂肪细胞平台上的合成有机小分子收集，以发现2型糖尿病型糖尿病（T2DM）的新型治疗药物（T2DM）和肥胖症。来自内脏（中央腹部仓库）起源的分化人脂肪细胞受到测试化合物的挑战，以发现触发内源性脂联素分泌的小分子。脂联素是与肥胖相关疾病中既定的生物标志物和因果介质。肥胖和糖尿病患者的体内脂肪因子的血浆浓度降低。因此，已提出上源性内源性脂联素的表达和分泌是与肥胖相关疾病的高优先性治疗策略。这项工作的最终目的是基于永生和原发性人内脏脂肪细胞的人类脂肪细胞驱动的药物发现平台，以发现肥胖，糖尿病和相关代谢性疾病的新型脂联素促脂蛋白，以及因继发性并发症而产生的疾病。该计划的关键要素是DBM的核心原则，即使用生物学和疾病的人类细胞平台来“降低风险”从头药物发现计划。该核心原理反映了DBM独特的角度，方法和提供药物发现空间的供应。来自正常供体和2型糖尿病患者的原发性和不朽的人类前脂肪细胞通过采用新型分化培养基的专利保护过程来区分。 DBM认为，成功的从头药物发现计划必须使用与疾病相关的人类细胞平台和与疾病相关的靶/表型终点（即分泌人脂联素的人脂肪细胞）。肥胖和与肥胖有关的疾病，包括T2DM，动脉粥样硬化，心血管疾病，脂肪肝病以及糖尿病性高血糖损伤的眼睛，心脏，肾脏和周围神经在美国以及发达国家以及发达的世界以及精确的巨大的疾病以及社会成本的巨大疾病和成本。对于新的治疗药物而言，存在着巨大的未满足临床需求，以打击这些疾病，尤其是在阿拉巴马州DBM居住在“东南糖尿病带”中心的阿拉巴马州。代谢性疾病的药物管道处于危险状态，大多数用于与肥胖相关疾病的管道药物仅因不确定的减肥副作用而简单地重新品牌，再生或合并。这些新的或重新塑造的用于代谢疾病的新药或重新塑造的药物已经失败并被放弃。有迫切需要和机会窗口将新陈代谢疾病通过新颖和创新的计划重新构成药物发现工作。 DBM通过以下主要项目里程碑提高了未满足的需求：（1）建立一个强大的分化人类内脏脂肪细胞药物发现平台； （2）设计，优化和实施从头毒品发现HTS友好的生物测定； （3）筛选DBM分子文库中的60,000种合成有机化合物，以发现新型内源性脂联素促分泌素； （4）从主要的HTS生物测定中验证推定的命中，并具有健壮的临界路径； （5）对经过验证的HIT化合物进行化学信息学，以识别值得更深入评估和分析的命中型化学类别。 DBM已经是该筛查目标的10％，并且已经对我们关键路径的早期输出进行了验证和化学信息学。 DBM寻求SBIR资金来加深和加速这种重要的代谢疾病药物发现计划。