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

描述（由申请人提供）：在原发性、转移性和耐药肿瘤表型中检测到异常活性Stat 3，并且是促进癌症发展和进展的事件的主要调节因子。我们和其他人的实质性工作已经证实，Stat 3选择性抑制剂将对各种人类癌症有治疗作用。我们的初步概念验证研究证明了主要Stat 3抑制剂S3 I-201和S3 I-201.1066在人类乳腺癌小鼠异种移植物中的强大抗肿瘤作用。在本研究中，BP-1-102和其他衍生自S3 I-201.1066的BP系列药物的生化、生物学和抗肿瘤活性进行了表征，发现其对异常Stat 3活性具有强抑制活性，结合亲和力（KD）为504 nM， IC_（50）值为0.7-15？M. BP-1- 102、XW-1-053和SH-04-54在亚微摩尔浓度（0.7-5 μ mol/L）时能抑制细胞内外Stat 3 DNA结合活性，并诱导抗肿瘤细胞作用。（三）活动。最初的体内试验显示BP-1-102强烈抑制小鼠异种移植物中人乳腺肿瘤的生长。这些非常有前途的新化学实体是迄今为止发现的最有效的Stat 3抑制剂之一。我们的目标是对主要药物与Stat 3的结合进行严格的结构分析，以获得结构数据，这些数据将支持假设驱动的密集药物化学工作，以产生临床开发的最佳参数的药物。我们假设优化的类似物将有效地抑制肿瘤细胞中的Stat 3活性和功能，具有合适的体内生物利用度，并且在人肿瘤异种移植物中具有高的抗肿瘤功效。为了实现目标和目标，将通过化学、结构分析、生物化学/生物学和药理学工作进行迭代优化。目标1和2中药物特性研究的数据将反馈到化学中，以指导优化和重复循环，直至确定合适的药物，并将在目标3中使用小鼠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研究，或者将1-2种候选药物授权给制药公司进行进一步的临床前开发和最终的临床试验。 公共卫生相关性：该提案旨在从BP系列异常活性信号转导和转录激活因子（Stat）3的新型抑制剂中获得临床候选药物，这些抑制剂已被证明可以抑制小鼠中人类乳腺肿瘤异种移植物的生长。

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. PUBLIC HEALTH RELEVANCE: The proposal seeks to derive clinical drug candidates from the BP-series of novel inhibitors of aberrantly-active Signal Transducer and Activator of Transcription (Stat)3, which have proven to inhibit the growth of human breast tumor xenografts in mice.