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药物，年销售额超过13亿美元。然而，目前可用的肽库仅对大约一半的生长激素分泌肿瘤患者有效，并且类癌肿瘤患者迅速对药物产生耐药性。这些试剂通过刺激G蛋白偶联受体（GPCR）sst 2A以激活Gi而起作用，但它们也引起受体的脱敏和内化，导致反应性降低。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，但不诱导内化或脱敏将正常化激素水平在更大比例的患者和患者没有充分控制目前可用的代理。在这里，我们建议通过使用受体内化和位点特异性磷酸化的测定来测试这一假设，以指导非肽口服活性生长抑素偏向激动剂的药物化学优化，其目标是为许多患有这些肿瘤的患者提供更好的治疗选择。这种方法基于我们最近的观察，即非肽L-779，976是具有强Gi活化的偏性生长抑素受体激动剂，但与肽激动剂相比，更快速地释放募集的2-arrestin和减少细胞表面受体的损失。在第一阶段，我们建议将这种药理学特性扩展到一个不同的面板的非肽类生长抑素激动剂，目的是证明可行性的测定，以支持药物化学和优先级铅化学系列随后优化的药理学和药学特性在第二阶段。这将包括严格测量其内在功效和诱导受体脱敏的能力--这类重要疗法的文献中令人惊讶地缺乏基本药理学数据。II期工作产生的产品将是一种新型口服化合物（或多种化合物），可用于临床前毒理学研究，为开始临床开发做准备。除了改善的临床功效之外，与昂贵的肽贮库制剂相比，这种口服药剂还将减少对医生办公室访问的需要，消除贮库注射的疼痛和不适，并且降低制造成本。除了创造一种新的治疗药物，这种方法是创新的，在前瞻性地使用受体调节测定，以指导早期的药物化学工作，而不是回顾性分析的一个或两个化合物，已经在临床上取得成功。GPCR具有许多共同的调控和信号传导机制，是人类基因组中最大的基因家族，也是药物发现的丰富来源。因此，如果成功，这项工作的影响不仅是为激素分泌肿瘤患者提供改进的药物，而且还将为优化靶向其他GPCR的激动剂药物提供一种新的通用策略。 公共卫生相关性：该项目使用受体内化、位点特异性磷酸化、脱敏和内在功效的测定来指导生长抑素受体sst 2A的新型口服可利用的偏向激动剂的设计和合成，其具有改善的功效和减少的脱敏，用于治疗激素分泌肿瘤。如果成功，这项工作将为许多其他GPCR药物靶标的激动剂优化提供一般策略。

DESCRIPTION (provided by applicant): Analogs of the neuropeptide somatostatin are important therapeutics for the treatment of hormone secreting tumors with annual sales in excess of $1.3B. However, currently available peptide depots are only effective in approximately half the patients with growth hormone secreting tumors and patients with carcinoid tumors rapidly become resistant to the drug. These agents act by stimulating a G protein coupled receptor (GPCR) sst2A to activate Gi, but they also cause desensitization and internalization of the receptor resulting in reduced responsiveness. We hypothesize that biased agonists of somatostatin receptor that maintain strong Gi activation but do not induce internalization or desensitization would normalize hormone levels in a greater percentage of patients and in patients not adequately controlled by currently available agents. Here we propose to test this hypothesis by using assays for receptor internalization and site-specific phosphorylation to guide medicinal chemistry optimization of nonpeptide orally active somatostatin biased agonists with the goal of providing improved therapeutic options for many patients with these tumors. This approach is premised on our recent observations that the nonpeptide L-779,976 is a biased somatostatin receptor agonist with strong Gi activation, but more rapid release of recruited 2-arrestin and reduced loss of cell surface receptor compared to peptide agonists. In Phase I we propose to extend this pharmacologic characterization to a diverse panel of nonpeptide somatostatin agonists with the goal of demonstrating feasibility of the assays to support medicinal chemistry and prioritizing lead chemical series for subsequent optimization of both pharmacologic and pharmaceutical properties in Phase II. This will include rigorous measurement of their intrinsic efficacy and ability to induce receptor desensitization-- fundamental pharmacologic data that is surprisingly lacking in the literature for this important class of therapeutics. The product resulting from the Phase II efforts will be a novel orally available compound (or compounds) ready for preclinical toxicology studies in preparation to begin clinical development. In addition to improved clinical efficacy such oral agents would also reduce the need for physician office visits, eliminate the pain and discomfort of depot injections, and lower manufacturing costs compared to expensive peptide depot formulations. Beyond the creation of a novel therapeutic agent, this approach is innovative in the prospective use of receptor regulatory assays to guide early medicinal chemistry efforts, rather than the retrospective analysis of one or two compounds that have already succeeded in the clinic. GPCRs share many common regulatory and signaling mechanisms and are both the largest gene family in the human genome and a rich source of proven targets for drug discovery. Therefore, if successful, the impact of this work not only be to provide improved agents for patients with hormone secreting tumors, but it will also exemplify a novel and general strategy for optimizing agonist drugs targeting other GPCRs. PUBLIC HEALTH RELEVANCE: This project uses assays for receptor internalization, site specific phosphorylation, desensitization & intrinsic efficacy to guide design and synthesis of novel orally available biased agonists of the somatostatin receptor sst2A with improved efficacy and reduced desensitization for the treatment of hormone secreting tumors. If successful, this work would provide a general strategy for agonist optimization of many additional GPCR drug targets.