Potent organometallic inhibitors of Signal Transducer and Activator of Transcript

描述（由申请人提供）：目前急性髓性白血病（AML）的治疗方法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%，复发的癌症与预后不良有关。对新的AML治疗方案的需求尚未得到满足。信号转导和转录激活因子3 （STAT3）蛋白是治疗侵袭性AML的潜在强有力的新治疗靶点。STAT3活性水平升高通过抑制细胞凋亡、降低免疫反应和促进耐药来加速肿瘤进展和增加致死率。STAT3的功能依赖于其Src同源性2 （SH2）结构域与含磷酸酪氨酸肽的结合。SH2结构域是一个常见的蛋白折叠，在与人类疾病相关的许多信号通路中发挥作用，开发针对SH2结构域的强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巨大的有益影响，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“不可药物”蛋白质靶点的例子：它们在浅结合口袋中通过微弱的、短暂的相互作用起作用，并且抵抗小分子的抑制。尽管如此，STAT3抑制剂与对肿瘤生长的理想影响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靶向STAT3，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-无机混合分子作为STAT3的特异性和有效抑制剂。通过结合分子识别和无机配体配位，我们将设计出靶向STAT3的候选药物，其效力和特异性将显著提高。在这笔资金的初始资助下，我们将证明新的抑制剂结构的有效结合及其对活细胞中STAT3功能的影响。我们将通过细胞凋亡激活和抑制AML集落形成的实验来评估治疗潜力，这些研究将为未来的动物和临床前研究奠定坚实的基础。这一应用将确立有机-无机杂合物作为一种强大的、概念上的新型潜在药物分子，在人类健康方面具有深远的应用和可能性。

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.