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

用于抗癌治疗的水杨酸小分子 Stat3 抑制剂

• 批准号: 9069481
• 负责人: James K Turkson
• 金额: $ 48.06万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069481
• 关键词: Affinity; Back; Binding; Biochemical; Biochemistry; Biological; Biological Assay; Biological Availability; Biological Process; Biology; Brain; Breast; Breast Cancer Model; Cells; Characteristics; Chemicals; Chemistry; Clinic; Clinical; Colon; DNA Binding; Data; Development; Dimerization; Drug resistance; Electrophoretic Mobility Shift Assay; Event; Generations; Glioblastoma; Goals; Growth; Human; In Vitro; Lead; Licensing; Lung; Lung Neoplasms; MDA MB 231; MDA-MB-468; Malignant Neoplasms; Mammary Neoplasms; Molecular; Mus; Nude Mice; Oral; Ovarian; Pancreas; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Phosphotyrosine; Property; Prostate; Proteins; Roentgen Rays; SKBR3; STAT protein; Safety; Salicylic Acids; Series; Solid; Stat3 protein; Structural Chemistry; Surface Plasmon Resonance; Testing; Toxic effect; Work; Xenograft Model; Xenograft procedure; analog; anti-cancer therapeutic; antitumor effect; base; cancer cell; cancer therapy; drug candidate; drug discovery; drug efficacy; feeding; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; meetings; melanoma; neoplastic cell; next generation; novel; novel therapeutics; pancreatic cancer cells; pre-clinical; programs; research clinical testing; small molecule; subcutaneous; transcription factor; tumor; tumor xenograft

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.

描述（由申请人提供）：在原发性、转移性和耐药性肿瘤表型中检测到异常活性的 Stat3，并且它是促进癌症发生和进展的事件的主要调节因子。我们和其他人的实质性工作已经证实 Stat3 选择性抑制剂对于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，主要的 Stat3 抑制剂 S3I-201 和 S3I-201.1066 在人类乳腺癌的小鼠异种移植物中具有强大的抗肿瘤作用。在本研究中，对 BP-1-102 和其他源自 S3I-201.1066 的 BP 系列药物的生化、生物和抗肿瘤活性进行了表征，发现对异常 Stat3 活性具有很强的抑制活性，结合亲和力 (KD) 为 504 nM， IC50 值为 0.7-15 μM。特别是，BP-1-102和新衍生的药物XW-1-053和SH-04-54抑制细胞内外异常的Stat3 DNA结合活性，并诱导针对具有亚微摩尔（0.7-5μM）活性的异常Stat3活性的恶性细胞的抗肿瘤细胞作用。初步体内测试表明 BP-1-102 强烈抑制小鼠异种移植物中人类乳腺肿瘤的生长。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 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，这些数据将支持假设驱动的密集药物化学工作，从而生成具有最佳参数的药物用于临床开发。我们假设优化的类似物将有效抑制肿瘤细胞中 Stat3 的活性和功能，具有适当的体内生物利用度，并在人类肿瘤异种移植物中具有较高的抗肿瘤功效。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，直到确定合适的药物，这将在目标 3 中使用人类乳腺癌小鼠模型进行体内抗肿瘤功效研究进行测试。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，或将 1-2 种候选药物授权给一家制药公司，以进行进一步的临床前开发和最终的临床测试。

项目成果

Heliotropiumides A and B, new phenolamides with N-carbamoyl putrescine moiety from Heliotropium foertherianum collected in Hawaii and their biological activities.

Heliotropiumides A 和 B，是从夏威夷收集的 Heliotropium fertherianum 中含有 N-氨基甲酰基腐胺部分的新型酚酰胺及其生物活性。

• DOI: 10.1016/j.bmcl.2017.09.021
• 发表时间: 2017
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Cai,You-Sheng;Sarotti,ArielM;Gündisch,Daniela;Kondratyuk,TamaraP;Pezzuto,JohnM;Turkson,James;Cao,Shugeng
• 通讯作者: Cao,Shugeng