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

描述（由申请人提供）：异常活跃的Stat3在原发性、转移性和耐药肿瘤表型中被检测到，是促进癌症发生和进展的事件的主要调节因子。我们和其他人的大量工作已经证实，stat3选择性抑制剂将对多种人类癌症具有治疗作用。我们的初步概念验证研究表明，Stat3先导抑制剂sgi -201和sgi -201.1066在人类乳腺癌小鼠异种移植物中具有很强的抗肿瘤作用。在本研究中，BP-1-102和其他bp系列药物衍生自sgi -201.1066，具有生物化学、生物学和抗肿瘤活性，并发现对异常Stat3活性具有较强的抑制活性，其结合亲和力（KD）为504 nM。

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.