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性肿瘤的重要疗法，年销售额约为 $1.7B。然而，目前可用的肽长效制剂仅对一半患有生长激素分泌肿瘤的患者有效，并且类癌患者会迅速对这些药物产生耐药性。生长抑素类似物通过刺激 sst2A（一种 G 蛋白偶联受体）发挥作用，但目前可用的药物通过受体内化引起脱敏，从而导致 功效降低或完全丧失。我们假设生长抑素受体的偏向激动剂能够维持强烈的Gi激活，但不会引起脱敏，可以使更大比例的患者的激素水平正常化，并提高目前可用药物无法充分控制的患者的疗效。在第一阶段，我们建议验证这一假设，使用受体激活和内化检测来鉴定不会引起脱敏的新型非肽、口服活性生长抑素偏向激动剂，目的是为这些肿瘤患者提供改进的治疗选择。在第一阶段，我们鉴定了几种小分子激动剂，它们确实是有效的 Gi 激活剂，但诱导受体内化和脱敏的倾向要小得多，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检测级联来识别具有所需特征的化合物，并且可以支持确定适合临床开发的候选药物所需的药物化学先导物优化工作。在第二阶段，我们将优化第一阶段确定的先导药物，以提供符合我们定义标准的新型口服候选药物，以进行支持临床开发所需的非临床毒理学研究。除了改善临床疗效外，口服制剂还可以减少医生就诊的需要，消除长效注射的疼痛和不适，并与昂贵的肽长效制剂相比降低制造成本。该项目有望提供一种新的具有成本效益的治疗剂，其具有新颖的药理学特征，可提高疗效。我们鉴定此类药物的方法是创新的，因为除了亲和力（或基于活性的）测定之外，我们还结合了受体调节测定（以检测受体脱敏）。这种检测组合将用于指导先导化合物优化工作。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，也是药物发现的经过验证的靶标的丰富来源，它们具有共同的调控和信号传导机制。因此，如果成功，这项工作不仅将为患有激素分泌肿瘤的患者提供改进的药物，而且还将支持优化激动剂药物的通用新策略，该激动剂药物可用于靶向许多其他 GPCR。