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，类癌肿瘤患者迅速对药物产生耐药性。这些药物通过刺激G蛋白偶联受体（GPCR） sst2A来激活Gi，但它们也会引起受体的脱敏和内化，从而降低反应性。我们假设，生长抑素受体的偏倚激动剂维持强烈的Gi激活，但不诱导内化或脱敏，将使更大比例的患者和目前可用药物无法充分控制的患者的激素水平正常化。在这里，我们建议通过受体内化和位点特异性磷酸化的检测来验证这一假设，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，目的是为许多患有这些肿瘤的患者提供更好的治疗选择。这种方法的前提是我们最近的观察，非肽L-779,976是一种偏向性生长抑素受体激动剂，具有强Gi激活，但与肽激动剂相比，招募的2-阻滞素释放更快，细胞表面受体的损失更少。在第一阶段，我们建议将这种药理学特征扩展到多种非肽生长抑素激动剂，目的是证明该分析的可行性，以支持药物化学，并优先考虑先导化学系列，以便在第二阶段进一步优化药理学和药物特性。这将包括严格测量它们的内在功效和诱导受体脱敏的能力——令人惊讶的是，在这类重要的治疗方法的文献中缺乏基本的药理学数据。II期的产品将是一种新的口服化合物（或多种化合物），用于临床前毒理学研究，准备开始临床开发。除了提高临床疗效外，这种口服药物还可以减少医生办公室就诊的需要，消除储存注射的疼痛和不适，并且与昂贵的肽库制剂相比，可以降低制造成本。除了创造一种新的治疗药物之外，这种方法在使用受体调节测定来指导早期药物化学工作方面具有创新性，而不是对已经在临床取得成功的一种或两种化合物进行回顾性分析。gpcr具有许多共同的调控和信号机制，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和通用的策略。

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