Rational Development of TCF/Beta-Catenin Antagonists

描述（由申请人提供）：我们提出发现和表征β-连环蛋白与TCF/LEF-1（T细胞因子/淋巴增强因子-1）相关的拮抗剂，TCF/LEF-1是WNT信号传导途径中的关键步骤。β-连环蛋白信号转导的失调与许多恶性肿瘤有关，这使得β-连环蛋白/TCF相互作用成为预防和治疗各种肿瘤（如乳腺癌、前列腺癌和结肠癌以及白血病）的有希望的靶点。β-连环蛋白犰狳重复结构域的结构得到了解决，单独和与TCF复合。我们强大的专有高通量对接技术使我们能够使用受体结构快速发现新型小分子配体。只有相对少量的化合物需要实验测试来确认活性。在项目第一阶段发现的初步命中将被彻底表征其治疗价值，并在第二阶段进一步优化为具有商业应用潜力的线索。我们在基于结构的配体发现和设计方面的专业知识，Molsoft结构生物学专家和Burnham研究所癌症生物学专家的协同努力，获得大量筛选化合物的机会，以及Molsoft使用其ICM生物计算平台开发的领先发现引擎，都将对我们事业的成功至关重要。

DESCRIPTION (provided by applicant): We propose to discover and characterize antagonists of the association of beta-catenin with TCF/LEF-1 (T-cell factor/lymphoid enhancer factor-1), a crucial step in WNT signaling pathway. Deregulation of beta-catenin signaling was implicated in a number of malignancies, which makes beta-catenin/TCF interaction a promising target for prevention and treatment of a variety of tumors, such as breast, prostate, and colon cancer as well as leukemia. The structure of the beta-catenin armadillo repeat domain was solved, alone and in complex with TCF. Our powerful proprietary high throughput docking technology allows us to rapidly discover novel small-molecule ligands using the receptor structure. Only a relatively small number of compounds will need experimental testing to confirm activity. Initial hits found in Phase I of the project will be thoroughly characterized for their therapeutic value and further optimized in Phase II into leads with high potential for commercial applications. Our expertise in the structure-based ligand discovery and design, the synergistic efforts of experts in structural biology at Molsoft and cancer biology at The Burnham Institute, access to large collections of screening compounds, and the lead discovery engine developed by Molsoft using its ICM biocomputing platform, will all be critical for the success of our undertaking.