Development of small molecule inhibitors of protein kinase D

蛋白激酶D小分子抑制剂的开发

• 批准号: 8010152
• 负责人: Qiming Jane Wang
• 金额: $ 29.47万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010152
• 关键词: 1,2-diacylglycerol; Agonist; Animals; Binding; Biological; Biological Assay; Biological Process; Cancer Model; Cardiac; Cell physiology; Cells; Chemicals; Clinical; Clinical Research; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diglycerides; Dimerization; Disease; Drug Kinetics; Enzyme Inhibition; Evaluation; Exhibits; Family; Fluorescence Polarization; Foundations; Future; G-Protein-Coupled Receptors; Generations; Goals; Growth Factor; Histone Deacetylase; Homo; Human; In Vitro; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Maximum Tolerated Dose; Mediating; Modification; Molecular; Mus; Neoplasm Metastasis; Nuclear; Nude Mice; Phorbol Esters; Phosphotransferases; Play; Property; Prostatic Neoplasms; Protein Isoforms; Proto-Oncogene Proteins c-akt; Regulatory Pathway; Reporting; Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Specificity; Spectrum Analysis; Surface Plasmon Resonance; Testing; Validation; Xenograft Model; analog; antitumor agent; base; cancer cell; dimer; high throughput screening; human disease; in vivo; inhibitor/antagonist; innovation; intermolecular interaction; migration; novel; protein kinase D; protein transport; public health relevance; receptor; response; second messenger; small molecule; subcutaneous; therapeutic target; tool; trafficking; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): Protein kinase D (PKD) is a novel family of the key second messenger diacylglycerol targets that can be activated by G-protein coupled receptor agonists and growth factors. The family of PKD - PKD1, 2 and 3 - plays important roles in many fundamental cellular processes. Deregulation of PKD has been implicated in multiple pathological conditions and cancer. However, the lack of a PKD-specific inhibitor has severely impeded our ability to understand PKD-specific signaling pathways and biological functions and to target it in human diseases. We have recently reported the first potent and selective small molecule inhibitor for PKD: benzoxoloazepinolone CID755673 that was identified through a high throughput screening campaign of 196,173 compounds. CID755673 is a pan-PKD inhibitor with submicromolar potencies. It was cell active and blocked the known biological actions of PKD and suppressed cancer-associated properties of proliferation, migration and invasion of prostate cancer cells. Importantly, this inhibitor was not competitive with ATP for enzyme inhibition and was highly selective for PKD when compared to at least 20 different kinases including CAMKII1, AKT, PKA and several PKC isoforms. Most critically, structural optimization of CID755673 has yielded a novel benzthiophene derivative kb-NB142-70 with low nanomolar potency and greater selectivity for PKD. We hypothesize that CID755673 can be optimized to a class of novel PKD inhibitors with unique mechanisms of action for potent and selective blockade of PKD functionality. Our long term goal is to establish a systemic approach to develop CID755673-derived probe molecules as innovative PKD inhibitors. Our proposed research strategies focus on lead optimization, mechanistic evaluation and in vivo efficacy assessment of CID755673 and its analogs. Three specific aims are proposed, representing the first major effort towards the development of potent and selective pharmacological ablative agents for PKD: Aim 1. Optimize CID755673 by structural modifications to access more potent and selective derivatives. Aim 2. Determine the molecular mechanisms underlying the exquisite selectivity of CID755673 and its analogs for PKD. Aim 3. Test the hypothesis that CID755673 and derivatives cause potent and selective blockade of PKD functionality in vivo. PUBLIC HEALTH RELEVANCE: The protein kinase D family is a novel receptor of the key second messenger diacylglycerol and an emerging therapeutic target for cancer and other diseases. Further understanding the role of PKD in biological processes and targeting it in human diseases have been severely impeded by the lack of a PKD-specific inhibitor that can be readily applied to cells and in animals. We have recently discovered the first potent and selective cell-active small molecule inhibitor for PKD - CID755673. We hypothesize that CID755673 can be optimized to generate a class of novel PKD inhibitors with unique mechanisms of action for potent and selective blockade of PKD functionality. The proposed studies focus on lead optimization, mechanistic evaluation and in vivo efficacy assessment of these novel chemical entities. The successful completion of the study will lead to a novel class of PKD inhibitors that can be used as powerful tools for dissecting PKD-mediated signaling pathways and functionalities in cells and animals. It will also provide the foundation for potential future clinical development of the compounds as novel antitumor agents.

描述（由申请人提供）：蛋白激酶D（PKD）是关键的第二信使二酰基甘油靶标的新家族，可以被G蛋白偶联受体激动剂和生长因子激活。 PKD 家族 - PKD1、2 和 3 - 在许多基本细胞过程中发挥着重要作用。 PKD 的失调与多种病理状况和癌症有关。然而，PKD 特异性抑制剂的缺乏严重阻碍了我们了解 PKD 特异性信号通路和生物学功能以及将其靶向治疗人类疾病的能力。我们最近报道了第一个有效的选择性 PKD 小分子抑制剂：苯并氧杂氮卓酮 CID755673，它是通过 196,173 种化合物的高通量筛选活动鉴定出来的。 CID755673 是一种具有亚微摩尔效力的泛 PKD 抑制剂。它具有细胞活性，可阻断 PKD 的已知生物学作用，并抑制前列腺癌细胞的增殖、迁移和侵袭等与癌症相关的特性。重要的是，该抑制剂在酶抑制方面不与 ATP 竞争，并且与至少 20 种不同的激酶（包括 CAMKII1、AKT、PKA 和几种 PKC 亚型）相比，对 PKD 具有高度选择性。最关键的是，CID755673 的结构优化产生了一种新型苯并噻吩衍生物 kb-NB142-70，具有低纳摩尔效力和更高的 PKD 选择性。我们假设 CID755673 可以优化为一类新型 PKD 抑制剂，具有独特的作用机制，可有效、选择性地阻断 PKD 功能。我们的长期目标是建立一种系统方法来开发 CID755673 衍生的探针分子作为创新的 PKD 抑制剂。我们提出的研究策略侧重于 CID755673 及其类似物的先导优化、机制评估和体内功效评估。提出了三个具体目标，代表了开发针对 PKD 的有效和选择性药理消融剂的第一个重大努力： 目标 1. 通过结构修饰优化 CID755673，以获得更有效和选择性的衍生物。目标 2. 确定 CID755673 及其类似物对 PKD 的精细选择性背后的分子机制。目标 3. 检验以下假设：CID755673 及其衍生物可在体内有效且选择性地阻断 PKD 功能。 公共卫生相关性：蛋白激酶 D 家族是关键第二信使二酰甘油的新型受体，也是癌症和其他疾病的新兴治疗靶点。由于缺乏可轻松应用于细胞和动物的 PKD 特异性抑制剂，进一步了解 PKD 在生物过程中的作用以及将其用于人类疾病中的作用受到严重阻碍。我们最近发现了第一个有效的、选择性的 PKD 细胞活性小分子抑制剂 - CID755673。我们假设 CID755673 可以经过优化，产生一类新型 PKD 抑制剂，其具有独特的作用机制，可有效、选择性地阻断 PKD 功能。拟议的研究重点是这些新型化学实体的先导化合物优化、机制评估和体内功效评估。该研究的成功完成将产生一类新型 PKD 抑制剂，可用作剖析细胞和动物中 PKD 介导的信号通路和功能的强大工具。它还将为这些化合物作为新型抗肿瘤药物的潜在临床开发奠定基础。