Potent organometallic inhibitors of Signal Transducer and Activator of Transcript

信号转导器和转录激活剂的有效有机金属抑制剂

• 批准号: 8384553
• 负责人: Zachary Thomas Ball
• 金额: $ 21.46万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-18 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384553
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Affinity; Amino Acids; Animals; Apoptosis; Binding; Binding Sites; Biochemical; Biological Assay; Biological Process; Bone Marrow Transplantation; Cancer Relapse; Cells; Child; Diagnosis; Disease; Disease Resistance; Drug Delivery Systems; Drug resistance; Employee Strikes; Foundations; Funding; Future; Grant; Health; Human; Hybrids; Immune response; In Vitro; Libraries; Life; Ligands; Link; Malignant Neoplasms; Mediating; Metals; Methods; Pain; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phosphotyrosine; Play; Procedures; Property; Proteins; Publishing; Relapse; Research Design; Resistance; Rhodium; Role; Screening procedure; Side; Signal Pathway; Signal Transduction; Solid; Specificity; Speed; Stat3 protein; Structure; Study models; Therapeutic; Therapeutic Intervention; Toxic effect; Transcript; Transducers; United States; base; cell growth; chemical synthesis; chemotherapy; design; drug candidate; drug development; human disease; improved; in vivo; inhibitor/antagonist; insight; molecular recognition; mouse model; new therapeutic target; novel strategies; novel therapeutics; outcome forecast; preclinical study; prevent; protein folding; protein protein interaction; small molecule; tumor; tumor growth; tumor progression; virtual

DESCRIPTION (provided by applicant): Current treatments for acute myeloid leukemia (AML) are inadequate to address the thousands of new cases diagnosed annually in the United States. Chemotherapy and bone marrow transplants are difficult and painful for patients, relapse rates approach 50%, and relapsed cancers are associated with poor prognosis. There is a large unmet need for new AML treatment options. The signal transducer and activator of transcription 3 (STAT3) protein is a potentially powerful new therapeutic target for the treatment of aggressive AML. Elevated levels of STAT3 activity speed tumor progression and increase lethality by inhibiting apoptosis, reducing immune responses, and facilitating drug resistance. STAT3 function is dependent on binding of its Src homology 2 (SH2) domain to a phosphotyrosine-containing peptide. The SH2 domain is a common protein fold that plays a role in numerous signaling pathways relevant to human disease, and developing potent drugs that target SH2 domains could have far-reaching impact. Unfortunately, while it is well understood that inhibiting STAT3 activity could have a dramatic and beneficial effect on tumor growth, developing drugs to target STAT3 is challenging. STAT3 and SH2-containing proteins in general, are examples of "undruggable" protein targets: they act through weak, transient interactions at shallow binding pockets and are resistant to inhibition with small molecules. Nonetheless, the link between STAT3 inhibitors and desirable effects on tumor growth has been conclusively demonstrated. Fundamentally new drug development approaches to effectively target STAT3 are needed to take advantage of this exciting new therapeutic opportunity. We plan to design, study, and develop hybrid organic-inorganic molecules as specific and potent inhibitors of STAT3. By combining molecular recognition with inorganic ligand coordination, we will design drug candidates with significantly improved potency and specificity in targeting STAT3. With initial funding from this grant, we will demonstrate potent binding of new inhibitor structures and their effect on STAT3 function in living cells. Assays for apoptosis activation and inhibition of AML colony formation will be conducted to evaluate therapeutic potential, and these studies will form a solid foundation for future animal and pre-clinical studies. This application wll establish organic-inorganic hybrids as a powerful and conceptually new class of potential drug molecules, with far-reaching applications and possibilities for applications in human health. PUBLIC HEALTH RELEVANCE: Acute myeloid leukemia (AML) afflicts thousands of new patients-including children- each year, but treatment options currently available are difficult and painful, and relapse is common. We will develop new drugs to treat AML by targeting the STAT3 protein, for which a link between STAT3 and aggressive AML cell growth has been established. Unfortunately, STAT3 does not possess features that make it easy to develop effective drug against it using traditional approaches, and so we will build drugs that target STAT3 using a completely new approach that combines the benefits of traditional drugs and those of metal-based drugs to create a hybrid drug that contains the best features of both.

描述(由申请人提供)：目前对急性髓系白血病(AML)的治疗方法不足以解决美国每年数千例新诊断病例。化疗和骨髓移植对患者来说是困难和痛苦的，复发率接近50%，复发的癌症与预后不良有关。对新的急性髓细胞白血病治疗方案有大量未得到满足的需求。信号转导和转录激活子3(STAT3)蛋白是治疗侵袭性AML的潜在新靶点。STAT3活性水平升高通过抑制细胞凋亡、减少免疫反应和促进耐药性来加速肿瘤进展和增加致命性。STAT3的功能依赖于其Src同源2(SH2)结构域与含有磷酸酪氨酸的多肽的结合。SH2结构域是一种常见的蛋白质折叠，在许多与人类疾病相关的信号通路中发挥作用，开发针对SH2结构域的有效药物可能具有深远的影响。不幸的是，尽管众所周知，抑制STAT3活性可能会对肿瘤生长产生戏剧性的有益影响，但开发针对STAT3的药物是具有挑战性的。一般说来，含有STAT3和SH2的蛋白质是“不能下药的”蛋白质靶标的例子：它们通过浅结合口袋的微弱的、短暂的相互作用起作用，并能抵抗小分子的抑制。尽管如此，STAT3抑制剂和对肿瘤生长的预期效果之间的联系已经得到了确凿的证明。从根本上说，需要新的药物开发方法来有效地针对STAT3，以利用这一令人兴奋的新治疗机会。我们计划设计、研究和开发有机-无机杂化分子作为STAT3的特异和有效的抑制剂。通过将分子识别与无机配体配位相结合，我们将设计具有显著提高的针对STAT3的效力和特异性的候选药物。利用这笔赠款的初始资金，我们将展示新的抑制物结构的有效结合及其对活细胞中STAT3功能的影响。将进行细胞凋亡激活和抑制AML集落形成的检测，以评估治疗潜力，这些研究将为未来的动物和临床前研究奠定坚实的基础。这一应用将建立有机-无机杂化作为一类强大的和概念上的新的潜在药物分子，具有深远的应用和在人类健康中应用的可能性。 公共卫生相关性：急性髓系白血病(AML)每年折磨着数以千计的新患者--包括儿童--但目前可用的治疗方案很困难，而且 疼痛，复发是很常见的。我们将通过靶向STAT3蛋白来开发治疗AML的新药，已经建立了STAT3与AML细胞侵袭性生长之间的联系。不幸的是，STAT3不具备使用传统方法开发有效药物的功能，因此我们将使用一种全新的方法来构建针对STAT3的药物，该方法结合了传统药物和基于金属的药物的优点，创造出一种包含两者最佳特征的混合药物。