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：
8461933
负责人：
Alexander Alphonse Parent
金额：
$ 4.72万
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/8461933
关键词：
Abbreviations Affinity Agonist Androgen Receptor Area Binding Biological Assay Boxing Carcinoma Cells Characteristics Clinic Complex Crystallography Cyclobutanes Development Endocrine Endocrinologist 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 Mammary Neoplasms 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 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 malignant breast neoplasm 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（CBIS），这些化合物与雌激素和雄激素受体的表面结合（ER和AR ）并直接抑制核激素受体（NHR）/共激活因子的相互作用。这些受体的传统拮抗剂在ER和AR的内部配体结合袋中结合，长期以来一直被用来治疗激素反应性的乳房和前列腺癌。尽管这些药物会产生初始的肿瘤回归，但在相对较短的时间（几个月至几年）突变和蛋白质调节的修饰中，最终使癌细胞避免了这种抑制作用，从而导致不受控制的肿瘤进展。然而，即使在这种激素 - 侵犯状态下，癌仍然是ER和AR依赖性的。因此，这些受体仍然是乳腺癌和前列腺癌疗法的重要靶标。假设CBI由于其直接抑制性，即使在传统拮抗剂失败之后，也可能证明有效的内分泌疗法。除了可能作为癌症治疗剂的效用外，这些化合物还应吸引分子内分泌学家作为可渗透探针，允许进一步研究NHR/共激活剂复合物。该项目旨在基于我们最近在NHR CBI地区取得的成功，尤其是CBI的嘧啶核心类别的项目，其成员是适度的时代和AR/共激活者的烦恼。为此，将合成多个小型CBI库，包括基于四芳基环丁烷核心的化合物，该化合物已经显示出有希望的结合特性。各种杂环和TER-PRYMIDINE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相互作用的性质，这又将允许第二代CBI库的基于结构的设计。所有合成化合物将使用基于体外和细胞的方法来测定其CBI活性，这将确定抑制活性并确认与受体表面结合。通过这种三管齐下的方法，希望能够在纳摩尔范围内发展具有亲和力的ER和AR选择性CBI的发展。由于乳腺癌和前列腺癌能够克服传统的雌激素和雄激素受体拮抗剂带来的抑制作用，因此需要采取新颖的方法来有效治疗这些癌症。通过与受体表面结合，共激活剂的结合抑制剂或CBI为内分泌相关癌症治疗提供了一种新方法，这种方法应在当前拮抗剂失败后保持可行。