Potent organometallic inhibitors of Signal Transducer and Activator of Transcript

描述（由申请人提供）：目前治疗急性髓性白血病（AML）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。对于新的AML治疗选择存在大量未满足的需求。信号转导子和转录激活子3（STAT 3）蛋白是治疗侵袭性AML的潜在强大的新治疗靶点。STAT 3活性水平的升高通过抑制细胞凋亡、减少免疫应答和促进耐药性来加速肿瘤进展并增加致死率。 STAT 3功能依赖于其Src同源2（SH 2）结构域与含磷酸酪氨酸的肽的结合。SH 2结构域是一种常见的蛋白质折叠，在与人类疾病相关的许多信号通路中发挥作用，开发靶向SH 2结构域的强效药物可能会产生深远的影响。不幸的是，尽管人们已经很好地理解抑制STAT 3活性可能对肿瘤生长产生巨大的有益影响，但开发靶向STAT 3的药物仍具有挑战性。一般来说，含STAT 3和SH 2的蛋白质是“不可用药的”蛋白质靶标的实例：它们通过在浅结合口袋处的弱的、瞬时的相互作用起作用，并且对小分子的抑制具有抗性。尽管如此，STAT 3抑制剂和对肿瘤生长的期望作用之间的联系已经得到了最终证明。从根本上说，需要有效靶向STAT 3的新药开发方法来利用这一令人兴奋的新治疗机会。我们计划设计，研究和开发杂化有机-无机分子作为特异性和有效的STAT 3抑制剂。通过将分子识别与无机配体配位相结合，我们将设计出在靶向STAT 3方面具有显著提高的效力和特异性的候选药物。通过这笔赠款的初始资金，我们将证明新抑制剂结构的有效结合及其对活细胞中STAT 3功能的影响。将进行细胞凋亡激活和AML集落形成抑制试验，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-无机杂化物作为一个强大的和概念上的新一类潜在的药物分子，具有深远的应用和应用于人类健康的可能性。

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.