Salicylic acid-based small-molecule Stat3 inhibitors for anticancer therapy

描述(申请人提供)：在原发、转移和耐药肿瘤表型中检测到异常活性的STAT3，它是促进癌症发展和进展的事件的主要调节者。我们和其他人的大量工作已经证实，STAT3选择性抑制剂在治疗各种人类癌症方面是有用的。我们最初的概念验证研究表明，在小鼠人乳腺癌移植瘤中，主要的STAT3抑制剂S3I-201和S3I-201.1066具有很强的抗肿瘤作用。在本研究中，从S3I-201.1066衍生的BP-1-102和其他BP系列化合物的生化、生物学和抗肿瘤活性进行了表征，发现它们对STAT3的异常活性具有很强的抑制活性，结合亲和力(Kd)为504nM， 特别是BP-1-102及其新化合物XW-1-053和SH-04-54在亚微摩尔(0.7-5M)活性范围内抑制细胞内外异常的STAT3 DNA结合活性，并诱导抗肿瘤细胞对具有异常STAT3活性的肿瘤细胞的杀伤作用。初步体内试验表明，BP-1-102在小鼠异种移植瘤中对人乳腺肿瘤的生长有强烈的抑制作用。这些非常有希望的新化学物质是迄今为止发现的最有效的STAT3抑制剂之一。我们的目标是对主要药物与STAT3的结合进行严格的结构分析，以获得结构数据，这些结构数据将支持假设驱动的密集药物化学努力，以产生临床开发的最佳参数的药物。我们推测，优化的类似物将有效地抑制肿瘤细胞中STAT3的活性和功能，具有合适的体内生物利用度，并在人肿瘤移植瘤中具有较高的抗肿瘤效果。为了实现目标和里程碑，将通过化学、结构分析、生物化学/生物学和药理学努力进行反复几轮优化。AIMS 1和AIMS 2中药物性质研究的数据将被反馈到化学中，以指导优化和重复循环，直到确定合适的药物为止，这将在AIMS 3中进行测试，使用小鼠的人乳腺癌模型进行体内抗肿瘤疗效研究。此后，我们的计划是通过NCI的Raid计划进行先进的临床前IND支持研究，或者将1-2个候选药物授权给一家制药公司进行进一步的临床前开发和最终的临床测试。

DESCRIPTION (provided by applicant): Aberrantly-active Stat3 is detected in primary, metastatic and drug resistant tumor phenotypes and is a master regulator of events that promote cancer development and progression. Substantive work from us and others has validated that Stat3-selective inhibitors would be therapeutically useful for a variety of human cancers. Initial proof-of-concept studies from us demonstrated strong antitumor effects of the lead Stat3 inhibitors, S3I-201 and S3I-201.1066 in mouse xenografts of human breast cancer. In the present study, BP-1-102 and other BP-series of agents derived from S3I-201.1066 were characterized for their biochemical, biological and antitumor activities and found to possess strong inhibitory activities against aberrant Stat3 activity, with binding affinity (KD) of 504 nM, and IC50 values of 0.7-15 ?M. In particular, BP-1- 102 and the newly-derived agents, XW-1-053 and SH-04-54 inhibited aberrant Stat3 DNA-binding activity outside and inside cells and induced antitumor cell effects against malignant cells harboring aberrant Stat3 activity at sub-micromolar (0.7-5 ?M) activities. Initial in vivo testing showed BP-1-102 strongly inhibit growth of human breast tumors in mouse xenografts. These very promising new chemical entities are among the most potent Stat3 inhibitors identified to date. Our objective is to pursue rigorous structural analyses of the leading agents' binding to Stat3 to derive structural data that will support a hypothesis-driven intensive medicinal chemistry effort to generate agents of optimum parameters for clinical development. We hypothesize that optimized analogs would potently inhibit Stat3 activity and functions in tumor cells, possess suitable in vivo bioavailability and have high antitumor efficacy in human tumor xenografts. To achieve the Aims and the Milestones, iterative rounds of optimization through chemistry, structural analysis, biochemistry/biology, and pharmacology efforts will be performed. Data from studies of the properties of agents in Aims 1 and 2 will be fed back into chemistry to guide the optimization and the cycle repeated until suitable agents are identified, which will be tested in Aim 3 for in vivo antitumor efficacy studies using human breast cancer models in mice. Our plan thereafter is to pursue advanced, pre-clinical IND enabling studies through the NCI's RAID program or to license out the 1-2 drug candidates to a pharmaceutical company for further pre-clinical development and eventually clinical testing.