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: 8057179
• 负责人: RICHARD SCOTT STRUTHERS
• 金额: $ 28.21万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057179
• 关键词: AIDS chemotherapy; Affinity; Agonist; Area; Arrestins; Binding; Biological Assay; Carcinoid Tumor; Cell Surface Receptors; Chemicals; Clinic; Clinical; Cyclic AMP; Data; Dementia; Depot Preparation; Development; Diabetic Nephropathy; Diabetic Retinopathy; Diarrhea; Disease; Drug Delivery Systems; Drug Formulations; Drug resistance; Epilepsy; Evaluation; Forskolin; G-Protein-Coupled Receptors; Gene Family; Goals; Government; Hormones; Human Genome; Injection of therapeutic agent; Laboratories; Lead; Licensing; Ligands; Literature; Measurement; Neuroendocrine Tumors; Neuropeptides; Octreotide; Office Visits; Oral; Pain; Patient Agents; Patients; Peptides; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphorylation; Physiological; Pituitary-dependent Cushing' s disease; Positioning Attribute; Preparation; Property; Recruitment Activity; Regulation; Resistance; Role; Sales; Series; Signal Transduction; Site; Somatostatin; Somatostatin Receptor; Somatotrophin increased; Somatotropin; Source; Structure-Activity Relationship; System; Testing; Texas; Therapeutic; Therapeutic Agents; Toxicology; Treatment Efficacy; Universities; Work; adenoma; analog; analog L; arrestin 2; base; chronic pain; clinical efficacy; comparative efficacy; cost; desensitization; design; drug candidate; drug discovery; improved; innovation; novel; novel therapeutics; peptide analog; pre-clinical; prospective; receptor; receptor internalization; research clinical testing; somatostatin analog; therapeutic target; tumor

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.

描述（由申请人提供）：神经肽生长抑素的类似物是治疗激素分泌肿瘤的重要治疗方法，其年销售额超过$ 1.3B。但是，目前可用的肽库仅在大约一半的生长激素分泌肿瘤的患者中有效，并且类癌肿瘤患者迅速对药物具有抗药性。这些药物通过刺激G蛋白偶联受体（GPCR）SST2A来起作用，以激活GI，但它们也会引起受体的脱敏和内在化，从而降低了反应性。我们假设生长抑素受体的偏见激动剂具有强大的胃肠道激活，但不会诱导内在化或脱敏会使较大比例的患者和未经当前可用药物充分控制的患者中的激素水平正常化。在这里，我们建议通过使用受体内在化的测定和特异性磷酸化来检验这一假设，以指导非肽的药物化学优化非肽的口服活性生长抑制抑素偏置激动剂，目的是为许多患有这些肿瘤的患者提供改进的治疗选择。这种方法的前提是我们最近的观察结果是，非肽L-779,976是一种具有强gi激活的偏置生长抑素受体激动剂，但与肽激动剂相比，募集的2-次素的迅速释放和细胞表面受体的损失更快。在第一阶段，我们建议将这种药理特征扩展到多种非肽生长抑素激动剂，目的是证明测定法的可行性，以支持药物化学和优先级化学化学系列，以随后优化了II期药理和药物学特性。这将包括严格测量其内在功效和诱导受体脱敏的能力 - 基本的药理学数据，这是这种重要类型的治疗方法的文献缺乏的。第二阶段努力产生的产品将是一种新型的口服化合物（或化合物），准备用于临床前毒理学研究，准备开始临床发育。除了提高临床疗效外，与昂贵的肽仓库配方相比，该口服剂还将减少对医师办公室就诊的需求，消除仓库注射的疼痛和不适。除了创建一种新型的治疗剂外，这种方法在未来使用受体调节测定方面具有创新性来指导早期的药物化学工作，而不是对已经在诊所成功的一种或两种化合物进行回顾性分析。 GPCR具有许多常见的调节和信号传导机制，既是人类基因组中最大的基因家族，也是良好的药物发现靶标的来源。因此，如果成功的话，这项工作的影响不仅是为激素分泌肿瘤的患者提供改进的药物，而且还将体现出一种新颖的一般策略，以优化针对其他GPCR的激动剂药物。 公共卫生相关性：该项目使用测定法进行受体内在化，特定地点的磷酸化，脱敏和固有功效，以指导生长抑素受体SST2A的新型口服偏置激动剂的设计和综合，并提高了疗效，并降低了脱敏的脱敏，以治疗荷尔蒙分泌肿瘤的脱敏性。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。

项目成果

Discovery of nonpeptide 3,4-dihydroquinazoline-4-carboxamides as potent and selective sst2 agonists.

• DOI: 10.1016/j.bmcl.2020.127391
• 发表时间: 2020-09-01
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Zhao J;Wang S;Han S;Kim SH;Kusnetzow AK;Nguyen J;Rico-Bautista E;Tan H;Betz SF;Scott Struthers R;Zhu Y
• 通讯作者: Zhu Y