Development of Wnt Pathway Inhibitors for Colorectal Cancer

描述（由申请人提供）：StemSynergy Therapeutics Inc. （SSTI）是一家生物制药公司，专注于发现、开发和商业化针对干细胞和癌症干细胞基本途径的药物。世界卫生组织估计，2007年确诊的癌症病例超过1200万例，近800万癌症患者将死于癌症。结直肠癌（CRC）是癌症导致死亡的第三大常见原因，有61万人死亡。Wnt信号通路的激活突变是CRC发生的最早事件，值得注意的是，超过90%的病例都存在这种突变。目前迫切需要Wnt通路的抑制剂来治疗结直肠癌和其他Wnt驱动的癌症。目前，没有fda批准的药物或处于后期临床试验的药物针对这一途径。SSTI开发了一种强大的生化筛选方法，利用Wnt途径的两个独立读数来识别Wnt抑制剂。通过高通量筛选评估两种Wnt通路蛋白（2-catenin和Axin）的稳定性，SSTI已经确定了通过激活酪蛋白激酶1a来调节Wnt信号的小分子。SSTI使用一种新颖的方法来优化先导物，开发了一系列具有更多药物性质的新先导化合物。我们成功的I期SBIR项目表明，这些化合物能有效抑制Wnt信号，降低多种人类CRC细胞系的活力，具有良好的ADMET特性，并显示出体内疗效。此外，SSTI能够利用药物化学开发二级（备用系列）。这两类小分子都代表了新的化学实体，我们的II期申请通过优化代谢、证明功效和在啮齿动物和非啮齿动物中进行安全性研究，概述了它们开发的下一个逻辑步骤。我们二期项目的总体目标是根据FDA晚期结直肠癌临床试验指南（ICH S9）证明IND申请所需的所有必要特性。由于市场上还没有针对Wnt通路的药物，SSTI有可能改善和延长全球数百万癌症患者的生命。综上所述，SSTI有机会将第一代Wnt抑制剂推向市场，并在全球抗癌药物市场中占据重要份额。

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.