Biased Agonism In GPCR Drug Discovery: Application To Somatostatin Agonists

GPCR 药物发现中的偏向激动：在生长抑素激动剂中的应用

• 批准号: 8589959
• 负责人: RICHARD SCOTT STRUTHERS
• 金额: $ 99.99万
• 依托单位: CRINETICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-12 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8589959
• 关键词: Affinity; Agonist; Bioavailable; Biological Assay; Biological Availability; Carcinoid Tumor; Cell Culture Techniques; Chemicals; Clinical; Cyclic AMP; Dementia; Development; Diabetic Retinopathy; Disease; Down-Regulation; Drug Formulations; Drug Kinetics; Drug Targeting; Drug resistance; Epilepsy; Evaluation; Exhibits; Eye; Family; Foundations; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; Gene Family; Goals; Government; Hormone Antagonists; Hormones; Human Genome; Immunohistochemistry; In Vitro; Injection Site Reaction; Injection of therapeutic agent; Insulin-Like Growth Factor I; Lead; Maximum Tolerated Dose; Modeling; Monitor; Neuroendocrine Tumors; Neuropeptides; Office Visits; Oral; Pain; Pancreatic Adenoma; Patient Agents; Patients; Peptides; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Pituitary Neoplasms; Preparation; Property; Proteins; Rattus; Receptor Activation; Safety; Sales; Series; Serum; Signal Transduction; Solutions; Somatostatin; Somatostatin Receptor; Somatotropin; Source; Structure-Activity Relationship; Tachyphylaxis; Texas; Therapeutic; Therapeutic Agents; Toxic effect; Toxicology; Transplantation; Treatment Efficacy; Tumor Cell Line; Tumor Tissue; Universities; Western Blotting; Work; adenoma; analog; base; chronic pain; clinical efficacy; cost; cost effective; desensitization; drug candidate; drug discovery; improved; in vivo; innovation; meetings; novel; novel strategies; peptide analog; pre-clinical; public health relevance; receptor; receptor internalization; small molecule; somatostatin analog; therapy resistant; trafficking; tumor

DESCRIPTION (provided by applicant): Neuropeptide somatostatin analogs are important therapeutics for the treatment of hormone secreting tumors with annual sales of ~$1.7B. However, the currently available peptide depots are effective in only half the patients with growth hormone secreting tumors, and patients with carcinoids can rapidly become resistant to these drugs. Somatostatin analogs act by stimulating sst2A, a G protein coupled receptor, but the currently available agents cause desensitization via internalization of the receptor, resulting in reduced or complete loss of efficacy. We hypothesized that biased agonists of the somatostatin receptor that maintain strong Gi activation, but do not cause desensitization, would normalize hormone levels in a greater percentage of patients and improve efficacy in patients not adequately controlled by currently available agents. In Phase I, we proposed to validate this hypothesis, using assays for both receptor activation and internalization to identify new nonpeptide, orally-active somatostatin biased agonists that do not cause desensitization, with the goal of providing improved therapeutic options for patients with these tumors. In Phase I, we identified several small molecule agonists that are indeed potent activators of Gi, but with far less propensity for, or no evidence of inducing receptor internalization and desensitization. These proof of concept studies showed that we can identify compounds with the desired profile using our assay cascade, and can support the medicinal chemistry lead optimization efforts required to identify a candidate suitable for clinical development. In Phase II, we will optimize our leads identified in Phase I to deliver a novel orally available drug candidate, which meets our defined criteria, to undergo the non-clinical toxicology studies necessary to support clinical development. In addition to improved clinical efficacy, orally delivered agents would also reduce the need for physician office visits, eliminate the pain and discomfort of depot injections, and lower the manufacturing costs compared to expensive peptide depot formulations. This project promises to deliver a new cost effective therapeutic agent with a novel pharmacological profile that leads to improved efficacy. Our approach towards the identification of such an agent is innovative in that we are incorporating receptor regulatory assays (to detect receptor desensitization), in addition to affinity (or activity-based) assays. This combination of assays wil be used to guide lead optimization efforts. Importantly, the G protein coupled receptor family is the largest gene family in the human genome and a rich source of proven targets for drug discovery, which share common regulatory and signaling mechanisms. Therefore, if successful, this work will not only provide improved agents for patients with hormone secreting tumors, but will also support a general novel strategy for optimizing agonist drugs that can be exploited to target many other GPCRs.

描述（由申请人提供）：神经肽生长抑素类似物是治疗激素分泌肿瘤的重要治疗剂，年销售额约为$ 1.7B。但是，目前可用的肽库仅在一半的生长激素分泌肿瘤的患者中有效，而类癌患者可以迅速对这些药物具有抵抗力。生长抑素类似物通过刺激SST2A（一种G蛋白偶联受体）来起作用，但是当前可用的代理通过受体的内在化引起脱敏，从而导致脱敏 在降低或完全丧失疗效中。我们假设生长抑素受体的偏置激动剂保持强大的胃肠道激活，但不会引起脱敏，将使较大比例的患者的激素水平正常化，并提高无法通过当前可用药物充分控制的患者的疗效。在第一阶段，我们提出了使用受体激活和内在化的测定来验证这一假设，以鉴定不引起脱敏的新型非肽，口服活性的生长抑制蛋白偏置激动剂，目的是为这些肿瘤患者提供改进的治疗选择。在第一阶段，我们确定了几个小分子激动剂，它们确实是GI的有效活化剂，但对受体内在化和脱敏的倾向却大大降低，或者没有证据。这些概念验证研究表明，我们可以使用我们的测定级联鉴定具有所需曲线的化合物，并可以支持确定适合临床开发的候选者所需的药物化学铅优化工作。在第二阶段，我们将优化在I期中确定的潜在客户，以提供符合我们确定标准的新型口服药物候选者，以接受支持临床开发所需的非临床毒理学研究。除了提高临床功效外，口服交付的药物还将减少医师办公室就诊的需求，消除仓库注射的疼痛和不适，并降低制造成本，而与昂贵的肽仓库配方相比。该项目有望通过新颖的药理特征提供新的成本有效治疗剂，从而提高功效。我们对这种药物进行鉴定的方法具有创新性，因为我们还合并了受体调节测定（以检测受体脱敏），除了亲和力（或基于活动）测定法。这种测定的组合将用于指导铅优化工作。重要的是，G蛋白偶联受体家族是人类基因组中最大的基因家族，并且是具有共同调节和信号传导机制的良好靶标的药物发现靶标。因此，如果成功的话，这项工作不仅将为肿瘤分泌激素的患者提供改进的药物，而且还将支持一种一般的新型策略，用于优化可用于针对许多其他GPCR的激动剂药物。