HTS Assays to Discover Selective Inhibitors of ADAM10 and 17

描述（由申请人提供）：约20-30%的乳腺癌患者的肿瘤过度表达人表皮生长因子受体（HER 2），这会导致侵袭性肿瘤表型和不良预后。ADAM蛋白酶由于其细胞外结构域的切割或HER 2配体的释放而负责HER 2信号传导的放大，这导致增殖和细胞凋亡的抑制。与HER 2信号放大有关的ADAM蛋白酶是ADAM 10和17;因此，抑制这些蛋白酶代表了消除乳腺癌中HER 2信号的可行方法。因此，本提案的具体目标将侧重于（1）筛选MLPCN文库， 与ADAM 10和17的双链体相互作用的抑制剂，和（2）药物化学优化初始先导物以开发ADAM 10和17的分子探针。我们的实验室是独特的定位，以实现这些目标，由于在暴露的结合抑制剂和探针，HTS，和蛋白酶的生物化学的发展的专业知识。我们还将与肽合成，HTS和药物化学领域的专家合作。该提案的目标的成功完成将导致发现针对ADAM 10和17的新型、有效和选择性的小分子探针。单独使用这些选择性分子探针或与其他工具（如siRNA，抗体和其他小分子抑制剂）组合使用，研究人员不仅能够研究ADAM蛋白酶家族单个成员的贡献，还能够研究ADAM蛋白酶控制的途径与其他途径的相互作用。

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.