HTS Assays to Discover Selective Inhibitors of ADAM10 and 17

描述(申请人提供)：大约20%-30%的乳腺癌患者患有过度表达人表皮生长因子受体(HER2)的肿瘤，这赋予了侵袭性肿瘤表型和不良预后。ADAM蛋白水解酶负责HER2信号的放大，因为它的胞外区被切割或HER2配体被释放，从而导致增殖和抑制细胞凋亡。与HER2信号放大有关的ADAM10和17是ADAM10和17；因此，抑制这些酶是消除乳腺癌HER2信号的一种可行的方法。因此，这项提案的具体目标将集中在(1)为以下目的筛选MLPCN图书馆 与ADAM10和17的暴露相互作用的抑制剂，以及(2)初始引线的药物化学优化，以开发ADAM10和17的分子探针。我们的实验室在开发暴露结合的抑制剂和探针、高温超导和蛋白酶的生物化学方面具有独特的优势，可以实现这些目标。我们还将与肽合成、高温超导和药物化学领域的专家合作。这项提议的目标的成功完成将导致发现针对ADAM10和17的新的、有效的和选择性的小分子探针。使用这些选择性的分子探针或结合其他工具，如siRNA、抗体和其他小分子抑制剂，研究人员将能够不仅能够研究亚当蛋白水解酶家族的单个成员的贡献，而且能够研究亚当蛋白水解酶控制的通路与其他与乳腺癌进展有关的通路的相互作用。

DESCRIPTION (provided by applicant): Approximately 20-30% of breast cancer patients have tumors that over-express human epidermal growth factor receptor (HER2), which confers an aggressive tumor phenotype and poor prognosis. ADAM proteases are responsible for amplification of HER2 signaling due to either cleavage of its extracellular domain or release of HER2 ligands, which leads to proliferation and inhibition of apoptosis. ADAM proteases implicated in amplification of HER2 signaling are ADAM10 and 17; therefore, inhibition of these proteases represents a viable approach to the abrogation of HER2 signaling in breast cancer. The specific aims of this proposal, therefore, will focus on (1) screening of the MLPCN library for inhibitors that interact with exposits of ADAM10 and 17, and (2) medicinal chemistry optimization of initial leads in order to develop molecular probes of ADAM10 and 17. Our laboratory is uniquely positioned to achieve these goals due to expertise in development of exposited-binding inhibitors and probes, HTS, and biochemistry of proteases. We will also collaborate with experts in the fields of peptide synthesis, HTS, and medicinal chemistry. The successful completion of the Aims of this proposal will lead to a discovery of novel, potent, and selective small molecule probes for ADAM10 and 17. Using these selective molecular probes alone or in combination with other tools, such as siRNA, antibodies, and other small molecule inhibitors, the researchers will be able to study contributions not only of individual members of the ADAM protease family, but also the interplay of ADAM protease-controlled pathways with other pathways implicated in the progression of breast cancer.