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。结直肠癌是癌症导致死亡的第二大常见原因，有120万人死亡。Wnt信号通路的激活突变是结直肠癌发生的最早事件，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。通过评估2-catenin和Axin两种Wnt通路蛋白的稳定性，SSTI筛选并鉴定出一种fda批准的化合物（SST-024），该化合物可有效抑制Wnt信号传导（EC50~10 nM）。SST-024此前被批准用于非癌症适应症。我们对SST-024的研究表明，它也是一种有效的结直肠癌细胞生长和活力抑制剂。重要的是，SST-024在抑制Wnt通路激活突变的结直肠癌细胞系（人类SW480细胞）生长方面的选择性比恢复野生型APC的基因相同的癌细胞（人类SW480细胞）高80倍。由于知识产权问题（SST-024已非专利）和对生物利用度的担忧，我们开始了一种虚拟筛选方法，以识别具有改进生物利用度和药物样特性的化合物。我们从这个筛选中得到的主要化合物之一SST-163，有效抑制Wnt信号传导并阻断Wnt驱动的癌细胞系的生长。SST-163还选择性地抑制SW480细胞在SW480APC细胞上的生长，这可能与癌细胞在正常组织上的治疗窗口相关。我们随后在小鼠异种移植模型中证明了使用SST-163阻断人SW480细胞生长的体内有效性。基于这些研究，我们启动了一个药物化学项目，专注于合成SST-163类似物，进一步优化其药物样性质。目前，我们的主要优化工作已经产生了更多的水溶性衍生物库，以供进一步评估。作为我们对SST-163类Wnt抑制剂的初步临床前表征的一部分，我们建议测试基于SST-163的文库对Wnt通路的效力、有利的毒理学特征和生物利用度模型。在这些研究中发现的最有希望的化合物将被测试其对一系列人类结直肠癌系的疗效，这些结直肠癌系含有激活的Wnt突变以及其他信号通路中的突变，以便确定我们的化合物可能对哪些患者最有效。最后，我们建议使用有前途的SST-163衍生物进行研究，以确定Wnt信号状态的药理学相关标记。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 represents the second most common cause of death due to cancer with 1.2 million deaths. Activating mutations in the Wnt signaling pathway are the earliest events in the genesis of colorectal cancer, 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, SSTI has screened and identified an FDA-approved compound (SST-024) that potently inhibits Wnt signaling (EC50~10 nM). SST-024 was previously approved for a non-cancer indication. Our studies of SST-024 indicate that it is also a potent inhibitor of colorectal cancer cell growth and viability. Importantly, SST-024 is 80 times more selective in inhibiting the growth of a colorectal cancer cell line with an activating mutation in the Wnt pathway (human SW480 cells) compared to a genetically identical cancer line that has wild-type APC restored (human SW480APC cells). Due to intellectual property issues (SST-024 is off- patent) and concerns about bioavailability, we embarked on a virtual screening approach to identify compounds with improved bioavailability and drug-like properties. One of our lead compounds from this screen, SST-163, potently inhibits Wnt signaling and blocks the growth of Wnt-driven cancer cell lines. SST-163 also selectively inhibits the growth of SW480 cells over SW480APC cells which would correlate with a therapeutic window for the treatment of cancer cells over normal tissue. We have subsequently shown in vivo efficacy using SST-163 to block the growth of human SW480 cells in a mouse xenograft model. Based on these studies, we initiated a medicinal chemistry program focused on the synthesis of SST-163 analogs that further optimized their drug-like properties. Currently, our lead optimization efforts have generated a library of more water soluble derivatives for further evaluation. As part of our initial preclinical characterization of the SST-163 class of Wnt inhibitors, we propose to test our SST-163-based library for potency against the Wnt pathway, for favorable toxicology profiles, and for bioavailability models. The most promising compounds identified in these studies will be tested for their efficacy on a series of human colorectal cancer lines that harbor activating Wnt mutations as well as mutations in other signaling pathways in order to identify the subset of patients for whom our compounds may be the most efficacious. Finally, we propose to perform studies using promising SST-163 derivatives to identify pharmacologically relevant markers for the status of Wnt signaling. 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. PUBLIC HEALTH RELEVANCE: Colorectal cancer is responsible for 1.2 million cases and 650,000 deaths each year. The Wnt pathway is a major growth pathway that plays a critical role in >90% of all cases and there are currently no inhibitors in the clinic. We intend to develop our lead compound Wnt pathway inhibitors through pre-clinical and clinical trials for a treatment of colorectal cancer.