HTS Assays to Discover Selective Inhibitors of ADAM10 and 17

HTS 检测发现 ADAM10 和 17 的选择性抑制剂

基本信息

批准号：
8262217
负责人：
Dmitriy Minond
金额：
$ 4.55万
依托单位：
TORREY PINES INST FOR MOLECULAR STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8262217
关键词：
ADAMTS Active Sites Address Antibodies Arts Binding Binding Sites Biochemistry Biological Assay Cancer Patient Cell Proliferation Cell surface Clinical Trials Collaborations Data Development Diagnosis Dimerization Disintegrins ERBB2 gene Enzyme Inhibitor Drugs Enzyme Inhibitors Epidermal Growth Factor Receptor Extracellular Domain Family Genes Goals Growth Human Individual Inhibition of Apoptosis Laboratories Lead Libraries Ligands MAP Kinase Gene Matrix Metalloproteinases Membrane Metalloproteases Molecular Probes Neoplasm Metastasis Outcome Pathway interactions Peptide Hydrolases Peptide Synthesis Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Play Positioning Attribute Post-Translational Protein Processing Proteins Research Research Personnel Role Screening procedure Signal Transduction Site Small Interfering RNA Specificity Structure Testing Toxic effect Woman anti-cancer therapeutic arthritis therapy base cancer cell collagenase 3 dimer high throughput screening inhibitor/antagonist malignant breast neoplasm member novel novel therapeutic intervention outcome forecast overexpression small molecule three dimensional structure tool tumor tumor progression

项目摘要

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.

描述（由申请人提供）：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，这导致肿瘤具有侵袭性表型和不良预后。 ADAM 蛋白酶负责通过裂解其胞外结构域或释放 HER2 配体来放大 HER2 信号传导，从而导致增殖和抑制细胞凋亡。与 HER2 信号放大有关的 ADAM 蛋白酶是 ADAM10 和 17；因此，抑制这些蛋白酶代表了消除乳腺癌中 HER2 信号传导的可行方法。因此，本提案的具体目标将集中在 (1) 筛选 MLPCN 文库与 ADAM10 和 17 的暴露相互作用的抑制剂，以及 (2) 初始先导化合物的药物化学优化，以开发 ADAM10 和 17 的分子探针。由于在开发暴露结合抑制剂方面的专业知识，我们的实验室在实现这些目标方面处于独特的地位以及探针、高温超导和蛋白酶的生物化学。我们还将与肽合成、高温超导和药物化学领域的专家合作。该提案目标的成功完成将导致针对 ADAM10 和 17 的新颖、有效和选择性小分子探针的发现。单独使用这些选择性分子探针或与其他工具（例如 siRNA、抗体和其他工具）结合使用通过使用小分子抑制剂，研究人员不仅能够研究 ADAM 蛋白酶家族各个成员的贡献，还能研究 ADAM 蛋白酶控制的通路与乳腺癌进展中涉及的其他通路的相互作用。