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Target Stat3 in pancreatic cancer using novel small molecule inhibitors

使用新型小分子抑制剂靶向胰腺癌中的 Stat3

基本信息

批准号：
7753175
负责人：
Chenglong Li
金额：
$ 16.1万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7753175
关键词：
Advanced Malignant Neoplasm Apoptosis Binding Breast Cancer Cell Cancer Cell Growth Cancer Prognosis Cancer cell line Cell Survival Chimera organism Clinical Research Clinical Trials Complex Country Crystallography Cytotoxic agent DNA Binding Development Diagnosis Dimerization Docking Dominant-Negative Mutation Drug resistance Event Future Genetic Transcription Goals Growth Hot Spot Human In Vitro Individual Laboratories Life Malignant Neoplasms Malignant neoplasm of pancreas Modeling Molecular Molecular Models Molecular Weight Mus Normal Cell Oligonucleotides Pancreas Pancreatic carcinoma Pathway interactions Patients Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pilot Projects Principal Investigator Proteins Reporting Roentgen Rays STAT3 gene Side Signal Transduction Site Staging Stat3 Signaling Pathway Stat3 protein Structure Survival Rate Testing Time Tumor Angiogenesis United States X-Ray Crystallography Xenograft Model analog base cancer cell cell growth design drug efficacy effective therapy improved in vivo inhibitor/antagonist innovation iterative design molecular modeling mutant neoplastic cell new therapeutic target novel novel therapeutic intervention outcome forecast pancreatic neoplasm pre-clinical public health relevance simulation small molecule small molecule libraries src Homology Region 2 Domain tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Each year about 32,000 individuals in the United States are diagnosed with pancreatic cancer and the prognosis is generally regarded as poor and the cancer of the pancreas is rarely curable. For patients with advanced cancers, the overall survival rate of all stages is less than 1% at 5 years with most patients dying within 1 year. Therefore, there is a critical need to develop more effective treatments for pancreatic cancer. The persistent activation of Stat3 is frequently detected in human cancers including pancreatic cancer but not in normal cells. Blocking signaling to Stat3 by dominant negative Stat3 mutants or antisense Stat3 oligonucleotides significantly inhibits cancer cell growth and renders cancer cells become sensitive to conventional cytotoxic agents, demonstrating that Stat3 may be crucial to the growth and drug resistance of cancer cells. We have recently developed novel small molecule compounds that inhibit Stat3 activities and opened a new door for possibly more effective treatment of pancreatic cancer. Our preliminary results demonstrated that our small molecules are potent inhibitors that blocks Stat3 transcription, Stat3 DNA binding activities, inhibits cell viability and induces apoptosis in pancreatic cancer cell lines with persistent Stat3 signaling. The objective of this proposal is to test inhibitory efficacy of the drug-like Stat3 inhibitors in pancreatic cancer cells in vitro and in a mouse tumor model. This pilot study is the first attempt to target Stat3 using non-peptide small molecule Stat3 inhibitors in pancreatic cancer. The pilot studies should establish the basis for future clinical study using novel pharmacological compounds that target Stat3, with the ultimate goal of treatment and improve the overall survival rate for human pancreatic carcinoma and extending the quality of healthy life for people in this country and around the world. The following specific aims will be studied: Aim 1. Design, synthesize, and test novel small molecules specifically targeting Stat3 SH2 dimerization site. Aim 2. Examine the inhibitory effects of the novel small molecule inhibitors that target Stat3 pathway in pancreatic cancer cells. Aim 3. Evaluate the inhibitory efficacy of the small molecule inhibitors that target Stat3 in a mouse tumor model. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is one of the most serious of cancers. There is an urgent need to develop more effective treatments for pancreatic cancer. The persistent activation of Stat3 is frequently detected in pancreatic cancer and contributes to the growth, tumor angiogenesis, and drug resistance of cancer cells. We have recently developed novel small molecule compounds, STA-21, LLL-3, and their structural analogue, LLL-12 that inhibit Stat3 activities and opened a new avenue for more effective therapy for pancreatic cancer that express persistent activation of Stat3. Our preliminary results indicate that our novel Stat3 inhibitors demonstrated potency in inhibiting cell viability of cancer cells expressing persistent activation of Stat3. We proposed to test the inhibitory effects of LLL-12 and its novel analogues in pancreatic cancer cells and in mouse tumor model. Our long-term goal is to target Stat3 as a new therapeutic approach for pancreatic cancer using novel small molecule inhibitors with the ultimate goal of improving the overall survival rate for human pancreatic cancer.

描述（由申请人提供）：美国每年约有32，000人被诊断患有胰腺癌，并且预后通常被认为是差的，并且胰腺癌很少是可治愈的。对于晚期癌症患者，所有阶段的5年总生存率不到1%，大多数患者在1年内死亡。因此，迫切需要开发更有效的胰腺癌治疗方法。Stat 3的持续激活经常在包括胰腺癌在内的人类癌症中检测到，但在正常细胞中未检测到。通过显性失活Stat 3突变体或反义Stat 3寡核苷酸阻断Stat 3信号传导可显著抑制癌细胞生长，并使癌细胞对常规细胞毒性剂变得敏感，表明Stat 3可能对癌细胞的生长和耐药性至关重要。我们最近开发了新型小分子化合物，抑制Stat 3活性，为可能更有效地治疗胰腺癌打开了一扇新的大门。我们的初步结果表明，我们的小分子是有效的抑制剂，阻断Stat 3转录，Stat 3 DNA结合活性，抑制细胞活力，并诱导胰腺癌细胞系与持续Stat 3信号的凋亡。本提案的目的是测试药物样Stat 3抑制剂在体外胰腺癌细胞和小鼠肿瘤模型中的抑制功效。这项初步研究是首次尝试在胰腺癌中使用非肽小分子Stat 3抑制剂靶向Stat 3。这些初步研究应该为未来使用靶向Stat 3的新型药理学化合物进行临床研究奠定基础，最终目标是治疗和提高人类胰腺癌的总生存率，并延长美国和世界各地人们的健康生活质量。将研究以下具体目标：目标1。设计、合成和测试特异性靶向Stat 3 SH 2二聚化位点的新型小分子。目标2.检查靶向胰腺癌细胞中Stat 3通路的新型小分子抑制剂的抑制作用。目标3.在小鼠肿瘤模型中评价靶向Stat 3的小分子抑制剂的抑制功效。胰腺癌是最严重的癌症之一。迫切需要开发更有效的胰腺癌治疗方法。Stat 3的持续激活经常在胰腺癌中检测到，并有助于癌细胞的生长、肿瘤血管生成和耐药性。我们最近开发了新型小分子化合物STA-21、LLL-3及其结构类似物LLL-12，它们抑制Stat 3活性，为表达Stat 3持续激活的胰腺癌的更有效治疗开辟了新途径。我们的初步结果表明，我们的新型Stat 3抑制剂在抑制表达Stat 3持续活化的癌细胞的细胞活力方面表现出效力。我们提出在胰腺癌细胞和小鼠肿瘤模型中测试LLL-12及其新型类似物的抑制作用。我们的长期目标是使用新型小分子抑制剂靶向Stat 3作为胰腺癌的新治疗方法，最终目标是提高人类胰腺癌的总生存率。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Characterization of molecular recognition of STAT3 SH2 domain inhibitors through molecular simulation.

DOI：
10.1002/jmr.1047
发表时间：
2011-03-01
期刊：
Journal of molecular recognition : JMR
影响因子：
0
作者：
Park, In-Hee;Li, Chenglong
通讯作者：
Li, Chenglong

A small molecule, LLL12 inhibits constitutive STAT3 and IL-6-induced STAT3 signaling and exhibits potent growth suppressive activity in human multiple myeloma cells.

DOI：
10.1002/ijc.26152
发表时间：
2012-03-15
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Lin, Li;Benson, Don M., Jr.;DeAngelis, Stephanie;Bakan, Courtney E.;Li, Pui-Kai;Li, Chenglong;Lin, Jiayuh
通讯作者：
Lin, Jiayuh

Fragment-based drug design and drug repositioning using multiple ligand simultaneous docking (MLSD): identifying celecoxib and template compounds as novel inhibitors of signal transducer and activator of transcription 3 (STAT3).

DOI：
10.1021/jm101330h
发表时间：
2011-08-11
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Li H;Liu A;Zhao Z;Xu Y;Lin J;Jou D;Li C
通讯作者：
Li C

Curcumin analogues exhibit enhanced growth suppressive activity in human pancreatic cancer cells.

DOI：
10.1097/cad.0b013e32832afc04
发表时间：
2009-07
期刊：
Anti-cancer drugs
影响因子：
2.3
作者：
Friedman L;Lin L;Ball S;Bekaii-Saab T;Fuchs J;Li PK;Li C;Lin J
通讯作者：
Lin J

Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells.

新型 STAT3 磷酸化抑制剂在胰腺癌细胞和乳腺癌细胞中表现出有效的生长抑制活性。

DOI：
10.1158/0008-5472.can-09-2468
发表时间：
2010-03-15
期刊：
Cancer research
影响因子：
11.2
作者：
Lin L;Hutzen B;Zuo M;Ball S;Deangelis S;Foust E;Pandit B;Ihnat MA;Shenoy SS;Kulp S;Li PK;Li C;Fuchs J;Lin J
通讯作者：
Lin J