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: 8727531
• 负责人: RICHARD SCOTT STRUTHERS
• 金额: $ 116.26万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8727531
• 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; Islet Cell Tumor; Lead; Maximum Tolerated Dose; Modeling; Monitor; Neuropeptides; Office Visits; Oral; Pain; 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（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药物，年销售额约为17亿美元。然而，目前可用的肽库仅对一半的生长激素分泌性肿瘤患者有效，并且类癌患者可迅速对这些药物产生耐药性。生长抑素类似物通过刺激sst 2A（一种G蛋白偶联受体）起作用，但目前可用的药剂通过受体的内化引起脱敏，导致 减少或完全丧失功效。我们假设，偏性促生长素抑制素受体激动剂，保持强烈的Gi激活，但不引起脱敏，将正常化激素水平在更大比例的患者和改善患者的疗效不充分控制目前可用的药物。在第一阶段，我们提议验证这一假设，使用受体激活和内化试验来鉴定不会导致脱敏的新型非肽类、口服活性生长激素抑制素偏向激动剂，目标是为这些肿瘤患者提供更好的治疗选择。在第一阶段，我们发现了几种小分子激动剂，它们确实是GI的强效激活剂，但诱导受体内化和脱敏的倾向要小得多，或者没有诱导受体内化和脱敏的证据。这些概念验证研究表明，我们可以使用我们的检测级联来鉴定具有所需特征的化合物，并且可以支持鉴定适合临床开发的候选药物所需的药物化学铅优化工作。在第二阶段，我们将优化我们在第一阶段确定的线索，以提供一种符合我们定义的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。除了改善的临床功效之外，口服递送的药剂还将减少对医生办公室访问的需要，消除储库注射的疼痛和不适，并且与昂贵的肽储库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，具有新的药理学特征，可提高疗效。我们对这种代理的识别方法是创新的，因为我们正在纳入受体调节测定（检测受体脱敏），除了亲和力（或基于活性）的测定。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，也是药物发现的已证实靶点的丰富来源，它们具有共同的调控和信号传导机制。因此，如果成功，这项工作不仅将为激素分泌肿瘤患者提供改进的药物，而且还将支持优化激动剂药物的一般新策略，这些药物可用于靶向许多其他GPCR。