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：
8416338
负责人：
Dmitriy Minond
金额：
$ 4.41万
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 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8416338
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 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 screening 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表达人类表皮生长因子受体（HER2）的肿瘤，该肿瘤赋予了侵袭性的肿瘤表型和预后不良。 Adam蛋白酶是由于其细胞外域的切割或HER2配体的释放而导致HER2信号传导扩增，这会导致增殖和抑制凋亡。与HER2信号的扩增有关的Adam蛋白酶为ADAM10和17。因此，对这些蛋白酶的抑制作用代表了一种可行的方法，可以消除乳腺癌中HER2信号传导。因此与ADAM10和17的展览相互作用的抑制剂，以及（2）初始铅的药物化学优化，以开发ADAM10和17的分子探针。由于在开发过蛋白酶，HTS，HTS和BioChemease proteases proteases的增生抑制剂和探针方面，我们的实验室具有独特的定位，可以实现这些目标。我们还将与肽合成，HTS和药物化学领域的专家合作。该提案的成功完成将导致发现ADAM10和17的新颖，有效和选择性的小分子探针。使用这些选择性分子探针或与其他工具结合使用，例如siRNA，抗体，抗体和其他小分子抑制剂，研究人员也将不得研究ADAM的构造，但ADAM构成了ADAM的成员，但会构成ADAM的成员，并构成ADAM的成员，并将其构成。具有其他途径的途径与乳腺癌的进展有关。