Therapeutic Small Molecule Modulators of G beta gama Signaling

G beta gama 信号传导的治疗性小分子调节剂

• 批准号: 8199535
• 负责人: Val S. Goodfellow
• 金额: $ 21.83万
• 依托单位: CALIFIA BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2012-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8199535
• 关键词: ADRBK1 gene; Absence of pain sensation; Adenylate Cyclase; Adrenergic Receptor; Adverse effects; Affinity; Agonist; Amino Acids; Animal Model; Binding; Biological; Biological Assay; Burn injury; Cardiovascular Diseases; Cells; Characteristics; Chemicals; Clinical Research; Collection; Computer Simulation; Computer software; Cysteine; Data; Development; Dissociation; Docking; Dose; Down-Regulation; Drug Kinetics; Dyes; Enzyme-Linked Immunosorbent Assay; Evaluation; Fluorescein; Functional disorder; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Grant; Heart; Heart Transplantation; Heart failure; Hot Spot; Human; Hydrolysis; In Vitro; Inflammation; Inhibitory Concentration 50; Intellectual Property; Lead; Legal patent; Libraries; Ligand Binding; Ligands; Light; Marketing; Mediating; Mediator of activation protein; Medical center; Microsomes; Molecular Weight; Morphine; Mus; Mutagenesis; National Cancer Institute; Opioid; Opioid Receptor; Oral; Pain; Patients; Peptide Phage Display Library; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphatidylinositols; Phospholipase C; Phosphotransferases; Physiological Processes; Play; Positioning Attribute; Process; Property; Protein Isoforms; Protein Subunits; Proteins; Publishing; Receptor Mediated Signal Transduction; Regulation; Research; Roentgen Rays; Role; Screening procedure; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Staging; Structure; Testing; Therapeutic; Triage; Universities; Withdrawal; adenylyl cyclase 1; base; chronic pain; cofactor; commercialization; crosslink; design; drug development; drug discovery; drug market; high throughput screening; in vitro Assay; in vitro activity; inhibitor/antagonist; interest; inward rectifier potassium channel; lead series; mouse model; novel; novel strategies; patch clamp; pre-clinical; prevent; professor; protein protein interaction; receptor; receptor coupling; small molecule; small molecule libraries; therapeutic target; virtual

DESCRIPTION (provided by applicant): G protein subunits play a central role in G-protein coupled receptor (GPCR)-mediated signal transduction processes. They act as cofactors in the activation of 7TM receptors and play direct roles in signaling to intracellular targets. GPCR signaling is extremely significant from a therapeutic standpoint; indeed, the majority of marketed pharmaceuticals target the receptor components of GPCRs. Less developed to date is the selective manipulation of intracellular subunit signaling, which could allow for the simultaneous modulation of multiple signaling pathways downstream of 7TM receptors. The commercialization of targeted modulators of subunit signaling would therefore have a tremendous impact on drug discovery paradigms. Professors Alan Smrcka, Burns Blaxall and Jean Bidlack at the University of Rochester Medical Center (URMC) have developed a novel strategy for the selective manipulation of G-protein subunit signaling that blocks - subunit binding to functional protein partners using small molecular weight compounds. They have demonstrated that these compounds are efficacious in animal models of heart failure, inflammation, and morphine-dependent analgesia. Califia Bio, Inc. is collaborating with the URMC team to develop these initial hit molecules into advanced chemical leads. These leads will ultimately be progressed into clinical studies for the treatment of cardiovascular disease and chronic pain. The current URMC hit molecules were identified from the NCI compound collection and lack drug-like characteristics as well as definitive intellectual property protection, which hampers their commercial development. In order to further develop novel small molecule inhibitors of subunit protein interactions, Califia Bio will utilize: 1) SAR gathered by URMC in high- throughput screening campaigns, 2) an X-ray crystal structure of previously identified small helical peptide inhibitor that binds to the subunit hot spot, 3) an X-ray crystal structure of a weak affinity small molecule ligand that binds to the same hot spot, and 4) specifically targeted reversible inhibitors designed to block a key active cysteine in the hot spot. After their initial design, potential inhibitors will be docked into the existing crystal structures and further triaged before synthesis by assessing their drug-like character and potential ADMET issues with proprietary software from Optibrium Ltd. A primary ELISA binding assay will be used to prioritize compounds, followed by secondary assays for inhibition of PLC activation and GRK2 G binding inhibition. -adrenergic receptor (BAR) dysfunction represents a hallmark abnormality of heart failure and interference of G-protein mediated GRK2 activity has been demonstrated to reverse the effects of (BAR) overstimulation. A patentable lead series will be identified, and the potency and selected ADME properties of this series will be optimized utilizing the above mentioned in vitro assays. In phase two, efficacy in animal models will be established and ADME properties will be optimized to allow for advanced preclinical development of potential therapeutics for treatment of heart failure and chronic pain. PUBLIC HEALTH RELEVANCE: This Phase I SBIR proposal is aimed at the discovery of potential small molecule therapeutics to treat heart failure. The mechanism involved may also be of interest for enhancing the efficacy and lessening the side effects of opioids used to treat chronic pain. Heart failure is estimated to be a $2 billion dollar drug market where there is great unmet therapeutic need, with approximately 5.7 million patients in the US, and 670,000 new cases per year. In end stage heart failure, only one half of patients will survive one year, and the only successful treatment is heart transplant, where only approximately 2000 patients per year are lucky enough to receive new hearts.

描述（由申请人提供）：G蛋白亚基在G蛋白偶联受体（GPCR）介导的信号转导过程中起着核心作用。它们在7TM受体的激活中充当辅因子，并在信号传导到细胞内靶标中起着直接的作用。从治疗的角度来看，GPCR信号传导非常重要。实际上，大多数销售的药品针对GPCR的受体成分。迄今为止不太发达的是对细胞内亚基信号的选择性操纵，这可以同时调节7TM受体下游的多个信号通路。因此，亚基信号的目标调节因子的商业化将对药物发现范式产生巨大影响。罗切斯特大学医学中心（URMC）的Alan Smrcka，Burns Blaxall和Jean Bidlack教授已经开发了一种新型策略，用于选择性操纵G蛋白亚基信号，该信号阻断了使用小分子量化合物的功能蛋白伴侣的亚基与功能蛋白伴侣的结合。他们已经证明，这些化合物在心力衰竭，炎症和吗啡依赖性镇痛的动物模型中有效。 Califia Beio，Inc。正在与URMC团队合作，将这些最初的热门分子开发为高级化学铅。这些潜在客户最终将进展为临床研究，以治疗心血管疾病和慢性疼痛。当前的URMC HIT分子是从NCI化合物收集中鉴定出来的，并且缺乏类似药物的特征以及确定的知识产权保护，这阻碍了其商业发展。为了进一步开发亚基蛋白相互作用的新型小分子抑制剂，Califia Bio将使用：1）由URMC收集的SAR在高吞吐量筛选运动中收集的SAR，2）先前鉴定的小型螺旋肽抑制剂的X射线晶体结构，该结构与X射线结构结合了X射线的小lig，3）与X射线结构结合，3）X射线结构。专门针对的可逆抑制剂旨在阻止热点键的关键活性半胱氨酸。 After their initial design, potential inhibitors will be docked into the existing crystal structures and further triaged before synthesis by assessing their drug-like character and potential ADMET issues with proprietary software from Optibrium Ltd. A primary ELISA binding assay will be used to prioritize compounds, followed by secondary assays for inhibition of PLC activation and GRK2 G binding inhibition. - 肾上腺素能受体（BAR）功能障碍表示心力衰竭的标志性异常和G蛋白介导的GRK2活性的干扰已被证明可以逆转（bar）过度刺激的影响。将确定可专利的铅系列，并利用上述体外测定法对该系列的效力和选择的ADME特性进行优化。在第二阶段，将建立动物模型的功效，并将优化ADME特性，以允许对潜在疗法的高级临床前开发用于治疗心力衰竭和慢性疼痛。 公共卫生相关性：此I阶段SBIR提案旨在发现潜在的小分子疗法来治疗心力衰竭。所涉及的机制也可能引起人们的兴趣，以提高疗效并降低用于治疗慢性疼痛的阿片类药物的副作用。据估计，心力衰竭是一个20亿美元的药物市场，在美国有很大的治疗需求，在美国约有570万患者，每年有67万例新病例。在最后阶段的心力衰竭中，只有一半的患者能够生存一年，而唯一成功的治疗是心脏移植，每年只有大约2000名患者幸运地接受新的心脏。