Biased Agonism In GPCR Drug Discovery: Application To Somatostatin Agonists

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疗法，年销售额约17亿美元。然而，目前可用的肽库只对一半的生长激素分泌型肿瘤患者有效，类癌患者可能很快就会对这些药物产生抗药性。生长抑素类似物通过刺激G蛋白偶联受体sst2A起作用，但目前可用的药物通过受体内化导致脱敏，结果 减少或完全丧失药效。我们假设，偏向的生长抑素受体激动剂维持强烈的GI激活，但不会导致脱敏，将使更大比例的患者的激素水平正常化，并提高目前现有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的分析来确定新的非肽、口服活性生长抑素偏向激动剂，这些激动剂不会导致脱敏，目的是为这些肿瘤患者提供更好的治疗选择。在第一阶段，我们确定了几种小分子激动剂，它们确实是GI的有效激活剂，但诱导受体内化和脱敏的倾向要小得多，或者没有证据表明。这些概念验证研究表明，我们可以使用我们的分析级联来识别具有所需轮廓的化合物，并可以支持药物化学领导的优化努力，以确定适合临床开发的候选化合物。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。除了提高临床疗效外，口服给药还将减少医生就诊的需要，消除仓库注射的痛苦和不适，并与昂贵的肽库配方相比降低制造成本。该项目承诺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，从而提高疗效。我们鉴定这种药物的方法是创新的，因为除了亲和力分析(或基于活性的分析)外，我们还纳入了受体调节分析(以检测受体脱敏)。这一分析组合将用于指导铅的优化工作。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，也是药物发现的丰富靶点，它们具有共同的调控和信号机制。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，还将支持一种通用的新策略，以优化可用于靶向许多其他GPCR的激动剂药物。

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.