Development of Wnt Pathway Inhibitors for Colorectal Cancer

结直肠癌Wnt通路抑制剂的开发

基本信息

批准号：
8549138
负责人：
Darren Orton
金额：
$ 85.91万
依托单位：
STEMSYNERGY THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-17 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8549138
关键词：
APC gene Adenomatous Polyposis Coli Animal Model Antineoplastic Agents Biochemical Biological Assay Biological Availability Biological Products Biotechnology Cancer Patient Cancer cell line Canis familiaris Cause of Death Cell Survival Cessation of life Chemicals Chemistry Clinic Clinical Clinical Data Clinical Trials Colorectal Cancer Complex Data Development Diagnosis Disease Drug Kinetics Drug Targeting Economic Burden Evaluation Event FDA approved Funding Generations Genetic Transcription Goals Growth Human In Vitro Laboratories Lead Legal patent Malignant Neoplasms Marketing Metabolism Modeling Molecular Biology Monkeys Mus Mutation Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Play Primates Process Property Proteins Reporter Rodent Role Safety Scaffolding Protein Series Signal Pathway Signal Transduction Small Business Innovation Research Grant Staging Stem cells Testing Therapeutic World Health Organization Xenograft procedure analog base cancer cell cancer stem cell casein kinase commercialization design drug development flexibility follow-up high throughput screening improved in vivo inhibitor/antagonist lead series metabolic abnormality assessment metastatic colorectal mouse model mutant novel novel strategies pre-clinical programs public health relevance safety study small molecule success

APC gene Adenomatous Polyposis Coli Animal Model Antineoplastic Agents Biochemical Biological Assay Biological Availability Biological Products Biotechnology Cancer Patient Cancer cell line Canis familiaris Cause of Death Cell Survival Cessation of life Chemicals Chemistry Clinic Clinical Clinical Data Clinical Trials Colorectal Cancer Complex Data Development Diagnosis Disease Drug Kinetics Drug Targeting Economic Burden Evaluation Event FDA approved Funding Generations Genetic Transcription Goals Growth Human In Vitro Laboratories Lead Legal patent Malignant Neoplasms Marketing Metabolism Modeling Molecular Biology Monkeys Mus Mutation Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Play Primates Process Property Proteins Reporter Rodent Role Safety Scaffolding Protein Series Signal Pathway Signal Transduction Small Business Innovation Research Grant Staging Stem cells Testing Therapeutic World Health Organization Xenograft procedure analog base cancer cell cancer stem cell casein kinase commercialization design drug development flexibility follow-up high throughput screening improved in vivo inhibitor/antagonist lead series metabolic abnormality assessment metastatic colorectal mouse model mutant novel novel strategies pre-clinical programs public health relevance safety study small molecule success

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项目摘要

DESCRIPTION (provided by applicant): StemSynergy Therapeutics Inc. (SSTI) is a biopharmaceutical company focused on the discovery, development, and commercialization of drugs that target pathways fundamental to stem cells and cancer stem cells. The World Health Organization estimates that over 12 million cases of cancer were diagnosed in 2007 and that nearly 8 million cancer patients will die of their disease. Colorectal cancer (CRC) represents the third most common cause of death due to cancer with 610,000 deaths. Activating mutations in the Wnt signaling pathway are the earliest events in the genesis of CRC, and, remarkably, are present in over 90% of all cases. There is an urgent need for inhibitors of the Wnt pathway for the treatment of colorectal cancer and other Wnt- driven cancers. Currently, there are no FDA-approved drugs or drugs in late-stage clinical trials that target this pathway. SSTI has developed a powerful biochemical screen to identify Wnt inhibitors utilizing two independent readouts of the Wnt pathway. By assessing the stability of two Wnt pathway proteins, 2-catenin and Axin in a high- throughput screen, SSTI has identified small molecules that regulate Wnt signaling via activation of Casein Kinase 1a. Using a novel approach to lead optimization, SSTI has developed a new series of lead compounds that have more drug-like properties. Our successful Phase I SBIR project demonstrated that these compounds potently inhibit Wnt signaling, decrease the viability of a variety of human CRC cell lines, have good ADMET properties, and show in vivo efficacy. Additionally, SSTI was able to develop a secondary (backup series) using medicinal chemistry. Both classes of small molecules represent new chemical entities and our Phase II application outlines the next logical steps in their development by optimizing metabolism, demonstrating efficacy and performing safety studies in rodent and non-rodent. Our overall goal of this Phase II project is to demonstrate all of the necessary properties for IND submission according to the FDA guidance (ICH S9) for clinical trials of advanced colorectal cancer. Because there are no drugs on the market that target the Wnt pathway, SSTI has the potential to improve and prolong the lives of millions of cancer patients worldwide. In summary, SSTI has the opportunity to bring to the market the first generation of Wnt inhibitors and capture a significant share of the global market for cancer drugs.

描述（由申请人提供）：Stemsynergy Therapeutics Inc.（SSTI）是一家生物制药公司，旨在针对针对干细胞和癌症干细胞基础的药物的发现，开发和商业化。世界卫生组织估计，2007年诊断出超过1200万例癌症病例，近800万癌症患者将死于疾病。结直肠癌（CRC）代表了由于癌症而导致的第三大死亡原因，死亡610,000例。 Wnt信号传导途径中的激活突变是CRC起源中最早的事件，并且在所有情况下，有90％以上的情况存在。迫切需要对Wnt途径的抑制剂治疗结直肠癌和其他WNT驱动的癌症。当前，在针对该途径的后期临床试验中，没有FDA批准的药物或药物。 SSTI开发了一个强大的生化屏幕，以使用WNT途径的两个独立读数来识别Wnt抑制剂。通过评估两个Wnt途径蛋白，2-catenin和Axin在高吞吐量筛选中的稳定性，SSTI已鉴定出通过激活酪蛋白激酶1a的激活来调节Wnt信号传导的小分子。 SSTI使用一种新型的方法来优化铅优化，开发了一系列具有更多类似药物的特性的铅化合物。我们成功的I期SBIR项目表明，这些化合物有效抑制Wnt信号，降低各种人CRC细胞系的生存能力，具有良好的ADMET特性并显示出体内功效。此外，SSTI能够使用药物化学开发次级（备用系列）。两类小分子都代表新的化学实体，我们的II期应用通过优化代谢，证明功效并在啮齿动物和非腐蚀性中进行安全研究来概述其发育中的下一个逻辑步骤。我们的II阶段项目的总体目标是根据FDA指南（ICH S9）进行晚期大肠癌临床试验的所有必要特性。由于市场上没有针对WNT途径的药物，因此SSTI有可能改善和延长全球数百万癌症患者的寿命。总而言之，SSTI有机会将第一代WNT抑制剂带入市场，并在全球癌症药物市场中占有很大份额。