Small-Molecule Disruptors of the Nuclear Hormone Receptor/Coactivator Interaction

核激素受体/共激活剂相互作用的小分子干扰剂

基本信息

批准号：
7673178
负责人：
Alexander Alphonse Parent
金额：
$ 4.62万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-16 至 2014-05-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7673178
关键词：
Abbreviations Affinity Agonist Androgen Receptor Area Binding Biological Assay Boxing Breast Carcinoma Cells Characteristics Clinic Complex Crystallography Cyclobutanes Development Endocrine Endocrinologist Estrogen Antagonists Estrogen Receptors Estrogens Evaluation Exhibits Failure Fluorescence Resonance Energy Transfer Future Gene Expression Regulation Generations Goals Hormone Responsive Hormones In Vitro Investigation Laboratories Libraries Ligand Binding Ligand Binding Domain Luciferases Malignant Neoplasms Malignant neoplasm of prostate Methods Modification Molecular Molecular Models Mutation N-terminal Nature Nitrogen Nuclear Hormone Receptors Nuclear Receptors Pathway interactions Peptide Library Peptides Pharmaceutical Preparations Process Prostate Cancer therapy Prostatic Neoplasms Proteins Pyrimidine Pyrimidines RNA Polymerase II Receptor Up-Regulation Refractory Regulation Relative (related person)Reporter Genes Research Side Steroid Receptors Structure Structure-Activity Relationship Surface System Therapeutic Time Treatment-Related Cancer Work analog base cancer cell design hormone therapy in vivo inhibitor/antagonist interest leucylleucine member molecular modeling novel novel strategies receptor scaffold small molecule success three dimensional structure time use trend tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): The aim of this project is the structure-based design, synthesis, and evaluation of small-molecule coactivator binding inhibitors (CBIs), compounds which bind to the surface of the estrogen and androgen receptors (ER and AR) and directly inhibit the nuclear hormone receptor(NHR)/coactivator interaction. Traditional antagonists of these receptors, which bind in the internal ligand binding pocket of ER and AR, have long been used to treat hormone-responsive breast and prostate cancers, respectively. Although these drugs produce initial tumor regression, in a relatively short amount of time (months to a few years) mutations and modifications in protein regulation eventually allow the cancer cell to circumvent this inhibition, leading to uncontrolled tumor progression. Nevertheless, even in this hormone-refractory state, the carcinomas continue to be ER and AR-dependent. Consequently, these receptors remain important targets for breast and prostate cancer therapies. It is hypothesized that CBIs, due to their direct inhibitory nature, could prove an effective endocrine therapy even after the failure of traditional antagonists. In addition to their possible utility as cancer therapeutics, these compounds should be of interest to molecular endocrinologists as cell- permeable probes that allow for further investigation of the NHR/coactivator complex. This project aims to build on the successes we have recently achieved in the NHR CBI area, especially those of the pyrimidine- core class of CBIs, members of which are modest ERa and AR/coactivator disrupters. To accomplish this, multiple, small CBI libraries will be synthesized, including compounds based on a tetra-aryl cyclobutane core that has already shown promising binding characteristics. Various heterocyclic and ter-pyrimidine scaffolds will also be used as core motifs. Current and future crystallographic efforts will be used to elucidate the nature of the NHR/CBI interaction, which in turn will allow for the structure-based design of second- generation CBI libraries. All synthesized compounds will be assayed for their CBI activity using in vitro and cell-based methods, which will determine inhibitory activity as well as confirm binding to the surface of the receptor. With this three-pronged approach, it is hoped that the development of ER and AR-selective CBIs with affinities in the nanomolar range will be achieved. Due to the ability of breast and prostate cancers to overcome inhibition brought about by traditional estrogen and androgen receptor antagonists, novel approaches are needed to effectively treat these cancers. By binding to the surface of the receptor, coactivator binding inhibitors or CBIs offer a new approach to endocrine-related cancer therapy, one that should remain viable after current antagonists fail.

描述（由申请人提供）：该项目的目的是基于结构的设计、合成和评估小分子共激活剂结合抑制剂（CBI），即与雌激素和雄激素受体（ER和AR）表面结合的化合物）并直接抑制核激素受体（NHR）/共激活剂相互作用。这些受体的传统拮抗剂结合在 ER 和 AR 的内部配体结合袋中，长期以来分别用于治疗激素反应性乳腺癌和前列腺癌。尽管这些药物最初可以使肿瘤消退，但在相对较短的时间内（几个月到几年）蛋白质调节的突变和修饰最终使癌细胞绕过这种抑制，导致肿瘤进展不受控制。然而，即使在这种激素抵抗状态下，癌症仍然依赖于 ER 和 AR。因此，这些受体仍然是乳腺癌和前列腺癌治疗的重要靶点。据推测，CBI 由于其直接抑制性质，即使在传统拮抗剂失败后也可以证明是一种有效的内分泌治疗。除了作为癌症治疗药物的可能用途外，分子内分泌学家应该对这些化合物作为细胞渗透性探针感兴趣，以进一步研究 NHR/共激活剂复合物。该项目旨在以我们最近在 NHR CBI 领域取得的成功为基础，特别是嘧啶核心类 CBI，其中的成员是适度的 ERa 和 AR/共激活剂干扰物。为了实现这一目标，将合成多个小型 CBI 文库，包括基于四芳基环丁烷核心的化合物，该核心已显示出有希望的结合特性。各种杂环和三联嘧啶支架也将用作核心基序。当前和未来的晶体学工作将用于阐明 NHR/CBI 相互作用的本质，这反过来又将允许第二代 CBI 文库的基于结构的设计。所有合成的化合物将使用体外和基于细胞的方法测定其 CBI 活性，这将确定抑制活性并确认与受体表面的结合。通过这种三管齐下的方法，希望能够开发出具有纳摩尔范围亲和力的 ER 和 AR 选择性 CBI。由于乳腺癌和前列腺癌能够克服传统雌激素和雄激素受体拮抗剂带来的抑制，因此需要新的方法来有效治疗这些癌症。通过与受体表面结合，共激活剂结合抑制剂或 CBI 为内分泌相关癌症治疗提供了一种新方法，该方法在当前拮抗剂失败后仍然可行。