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: 8547045
• 负责人: Zachary Thomas Ball
• 金额: $ 15.69万
• 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/8547045
• 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 Targeting; 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; 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; screening; 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.

描述（由申请人提供）：目前对急性髓性白血病（AML）的治疗不足以解决美国每年诊断的数千例新病例。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%，复发的癌症与不良预后相关。对新的 AML 治疗方案的需求仍有大量未满足的需求。信号转导子和转录激活子 3 (STAT3) 蛋白是治疗侵袭性 AML 的潜在强大新治疗靶点。 STAT3 活性水平升高可通过抑制细胞凋亡、减少免疫反应和促进耐药性来加速肿瘤进展并增加致死率。 STAT3 功能依赖于其 Src 同源 2 (SH2) 结构域与含磷酸酪氨酸的肽的结合。 SH2 结构域是一种常见的蛋白质折叠，在与人类疾病相关的众多信号通路中发挥作用，开发针对 SH2 结构域的有效药物可能会产生深远的影响。不幸的是，虽然众所周知抑制 STAT3 活性可能对肿瘤生长产生显着且有益的影响，但开发针对 STAT3 的药物仍具有挑战性。一般来说，含有 STAT3 和 SH2 的蛋白质是“不可成药”蛋白质靶标的例子：它们通过浅结合袋处的微弱、短暂的相互作用起作用，并且对小分子的抑制具有抵抗力。尽管如此，STAT3 抑制剂与肿瘤生长的理想效果之间的联系已得到最终证明。为了利用这一令人兴奋的新治疗机会，需要有效靶向 STAT3 的根本性新药物开发方法。我们计划设计、研究和开发混合有机-无机分子作为 STAT3 的特异性和有效抑制剂。通过将分子识别与无机配体协调相结合，我们将设计出靶向 STAT3 的效力和特异性显着提高的候选药物。借助这笔资助的初始资金，我们将证明新抑制剂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 AML 集落形成抑制的测定，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。该应用将建立有机-无机杂化物作为一种强大的、概念上新型的潜在药物分子，具有深远的应用和在人类健康中应用的可能性。

项目成果

Convenient analysis of protein modification by chemical blotting with fluorogenic "click" reagents.

使用荧光“点击”试剂通过化学印迹方便地分析蛋白质修饰。

• DOI: 10.1039/c5mb00510h
• 发表时间: 2015
• 期刊: Molecular bioSystems
• 作者: Ohata,Jun;Vohidov,Farrukh;Ball,ZacharyT
• 通讯作者: Ball,ZacharyT

Molecular recognition in protein modification with rhodium metallopeptides.

• DOI: 10.1016/j.cbpa.2014.12.017
• 发表时间: 2015-04
• 期刊: CURRENT OPINION IN CHEMICAL BIOLOGY
• 影响因子: 7.8
• 作者: Ball, Zachary T.

Luminogenic iridium azide complexes.

• DOI: 10.1039/c5cc06099k
• 发表时间: 2015-10-21
• 期刊: Chemical communications (Cambridge, England)
• 作者: Ohata J;Vohidov F;Aliyan A;Huang K;Martí AA;Ball ZT
• 通讯作者: Ball ZT

Assessing the intracellular fate of rhodium(ii) complexes.

评估铑(ii)络合物的细胞内命运。

• DOI: 10.1039/c6cc05192h
• 发表时间: 2016
• 期刊: Chemical communications (Cambridge, England)
• 作者: Minus,MatthewB;Kang,MarciK;Knudsen,SarahE;Liu,Wei;Krueger,MichaelJ;Smith,MorgenL;Redell,MicheleS;Ball,ZacharyT
• 通讯作者: Ball,ZacharyT