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

基本信息

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
项目类别：
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&apos 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

项目摘要

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性肿瘤的重要疗法，年销售额超过 $1.3B。然而，目前可用的肽长效制剂仅对大约一半的生长激素分泌肿瘤患者有效，并且类癌肿瘤患者很快就会对该药物产生耐药性。这些药物通过刺激 G 蛋白偶联受体 (GPCR) sst2A 来激活 Gi，但它们也会导致受体脱敏和内化，从而导致反应性降低。我们假设生长抑素受体的偏向激动剂维持强烈的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不能充分控制的患者的激素水平正常化。在这里，我们建议通过使用受体内化和位点特异性磷酸化测定来检验这一假设，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改进的治疗选择。这种方法的前提是我们最近观察到，非肽 L-779,976 是一种偏向生长抑素受体激动剂，具有强烈的 Gi 激活作用，但与肽激动剂相比，募集的 2-抑制蛋白的释放更快，细胞表面受体的损失减少。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，目的是证明支持药物化学的检测方法的可行性，并优先考虑先导化学系列，以便随后在第二阶段优化药理学和药物特性。这将包括严格测量其内在功效和诱导受体脱敏的能力——令人惊讶的是，这类重要治疗方法的文献中缺乏基本的药理学数据。 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，为开始临床开发做好准备。除了改善临床功效之外，此类口服制剂还可以减少医生就诊的需要，消除长效注射的疼痛和不适，并且与昂贵的肽长效制剂相比，可以降低制造成本。除了创造一种新型治疗剂之外，这种方法的创新在于前瞻性地使用受体调节测定来指导早期药物化学工作，而不是对已经在临床上取得成功的一两种化合物进行回顾性分析。 GPCR 具有许多共同的调控和信号传导机制，既是人类基因组中最大的基因家族，也是药物发现的经过验证的靶点的丰富来源。因此，如果成功，这项工作的影响不仅是为患有激素分泌肿瘤的患者提供改进的药物，而且还将举例说明优化针对其他 GPCR 的激动剂药物的新颖且通用的策略。公共健康相关性：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设计和合成新型口服生长抑素受体 sst2A 偏向激动剂，以提高疗效并减少脱敏，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 药物靶点的激动剂优化提供通用策略。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（3）

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

发现非肽 3,4-二氢喹唑啉-4-甲酰胺作为有效的选择性 sst2 激动剂。

DOI：
发表时间：
2020
期刊：
影响因子：
2.7
作者：
Zhao, Jian;Wang, Shimiao;Han, Sangdon;Kim, Sun Hee;Kusnetzow, Ana Karin;Nguyen, Julie;Rico;Tan, Hannah;Betz, Stephen F;Scott Struthers, R;Zhu, Yunfei
通讯作者：
Zhu, Yunfei

Discovery of substituted 3H-pyrido[2,3-d]pyrimidin-4-ones as potent, biased, and orally bioavailable sst2 agonist.

发现取代的 3H-吡啶并[2,3-d]嘧啶-4-酮作为有效、有偏倚且口服生物可利用的 sst2 激动剂。

DOI：
发表时间：
2020
期刊：
影响因子：
2.7
作者：
Zhao, Jian;Chen, Zhiyong;Kusnetzow, Ana Karin;Nguyen, Julie;Rico;Tan, Hannah;Betz, Stephen F;Struthers, R Scott;Zhu, Yunfei
通讯作者：
Zhu, Yunfei