权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Modeling, Synthesis, and Biological Evaluation of Potential RXT Selective Agonist

潜在 RXT 选择性激动剂的建模、合成和生物学评价

基本信息

批准号：
8035750
负责人：
Carl Edward Wagner
金额：
$ 45.75万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8035750
关键词：
Adverse effects Affinity Agonist Animals Apoptosis Attenuated Bexarotene Binding Biological Biological Assay Biological Markers Cell Culture Techniques Cells Chemoprotection Clinical Trials Colorectal Cancer Cutaneous Data Dose Drug Design Drug Kinetics Evaluation FDA approved Gene Expression Genes Homodimerization Human Hybrids Hypertriglyceridemia Hypothyroidism In Vitro Lead Ligand Binding Domain Ligands Lipids Literature Location Malignant neoplasm of prostate Mediating Metabolic Clearance Rate Methodology Microarray Analysis Modeling Molecular Biology Molecular Models Molecular Profiling Nuclear Receptors Oligonucleotide Microarrays Oncogenes Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Process Property RXR Rattus Regulation Renal carcinoma Reporting Repression Research Reverse Transcriptase Polymerase Chain Reaction Saccharomyces cerevisiae Signal Transduction Skeleton Specificity Students Study models System T-Cell Lymphoma Testing Thyroid Gland Toxic effect Training Triglycerides Two-Hybrid System Techniques Validation Yeasts analog base cancer cell clinical application clinically significant cytotoxicity enhancing factor functional group improved in vivo innovation malignant breast neoplasm model design molecular modeling novel receptor receptor binding tumor

项目摘要

We propose to employ rational drug design to synthesize novel retinoid X receptor (RXR) analogs (rexinoids) that preferentially bind to RXR, and are superior in biological potency and specificity to current rexinoids. These novel compounds will possess decreased toxicity as well as attenuated antagonism of other nuclear receptor pathways that employ RXR as a heterodimeric partner in transcriptional signaling. We will also utilize the newly synthesized rexinoid compounds to probe cancer cells to elucidate unique anti- proliferative/prodifferentiation genes that are regulated by RXR-mediated pathways. Our model synthetic skeleton is bexarotene, a potent FDA-approved RXR agonist used for treatment of cutaneous T cell lymphoma (CTCL); however, patients treated with this potent RXR-agonist often suffer from side effects like hypothyroidism, raised triglycerides, and cutaneous toxicity, presumably arising through alternate RXR-involved biological pathways. Thus it is constructive to develop novel rexinoids that would not provoke these untoward side effects. Through preliminary modeling studies, we will determine whether a given compound will associate effectively with the ligand-binding domain of RXR. For compounds passing these preliminary modeling studies, we will synthesize these analogs of bexarotene that incorporate novel atoms and functional groups at specific locations on the molecule in an attempt to create an RXR agonist that is not only selective for RXR, but does not induce negative side-effects in the proposed cell culture and animal studies. We will assay these unique agonist molecules in RXR mammalian-2-hybrid assays. Those analogs that induce robust RXR homodimerization will be further evaluated in an RXRE-mediated transcriptional assay system, to determine agonist activity. Analogs with the greatest potential as RXR agonists will also be tested for their proapoptotic ability and their lack of teratogenicity. Once we have identified lead RXR-agonists, we will assay in cell culture their ability to influence transcriptional signaling by other receptors, such as TR, that utilize RXR as a heterodimeric partner. The most specific RXR-homodimerization agonists will be examined for diminished clearance rates in vivo and novel metabolites in both in vitro and in vivo pharmacokinetic profiles. In vivo toxicity will be determined in the most promising of compounds by dosing and assaying lipid and TSH profiles in a rat model, the two pathways most dysregulated in patients undergoing bexarotene therapy. Finally, microarray analysis will be used to determine gene expression profiles of CTCL cells treated with bexarotene and select analogs. The genes that display the most responsive regulation (activation or repression) will be compared to bexarotene treated cells in an effort to identify those analogs with the potential to most effectively regulate the greatest number of biomarkers associated with chemoprotection. In addition to the above aims, this project will help train undergraduate research students who will design, model, synthesize, and test novel and innovative RXR analogs with potential clinical application and significance in the treatment of CTCL.

我们建议采用合理的药物设计，合成优先结合RXR的新型维甲酸X受体（RXR）类似物（rexinoids），并在生物效力和特异性上优于现有的rexinoids。这些新化合物将具有较低的毒性，并减弱对其他利用RXR作为异二聚体伙伴参与转录信号传导的核受体途径的拮抗作用。我们还将利用新合成的类雷克萨斯化合物探测癌细胞，以阐明受rxr介导途径调控的独特的抗增殖/前分化基因。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（11）

Development of Bexarotene Analogs for Treating Cutaneous T-Cell Lymphomas.

用于治疗皮肤T细胞淋巴瘤的链球烯类似物的发展。

DOI：
10.3390/cells12212575
发表时间：
2023-11-04
期刊：
Cells
影响因子：
6
作者：
通讯作者：

Dataset on the response of Hut78 cells to novel rexinoids.

DOI：
10.1016/j.dib.2018.09.012
发表时间：
2018-10
期刊：
Data in brief
影响因子：
1.2
作者：
Hackney Price J;Hanish BJ;Wagner CE;Kaneko I;Jurutka PW;Marshall PA
通讯作者：
Marshall PA

A novel gene expression analytics-based approach to structure aided design of rexinoids for development as next-generation cancer therapeutics.

DOI：
10.1016/j.steroids.2018.04.009
发表时间：
2018-07
期刊：
Steroids
影响因子：
2.7
作者：
Hanish BJ;Hackney Price JF;Kaneko I;Ma N;van der Vaart A;Wagner CE;Jurutka PW;Marshall PA
通讯作者：
Marshall PA

Evaluating Novel RXR Agonists That Induce ApoE and Tyrosine Hydroxylase in Cultured Human Glioblastoma Cells.

评估在培养的人胶质母细胞瘤细胞中诱导 ApoE 和酪氨酸羟化酶的新型 RXR 激动剂。

DOI：
10.1021/acschemneuro.0c00707
发表时间：
2021
期刊：
ACS chemical neuroscience
影响因子：
5
作者：
Mallick,Sanchita;Marshall,PamelaA;Wagner,CarlE;Heck,MichaelC;Sabir,ZhelaL;Sabir,MaryaS;Dussik,ChristoperM;Grozic,Aleksandra;Kaneko,Ichiro;Jurutka,PeterW
通讯作者：
Jurutka,PeterW

An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene.

DOI：
10.3390/ijms232416213
发表时间：
2022-12-19
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Jurutka, Peter W.;di Martino, Orsola;Reshi, Sabeeha;Mallick, Sanchita;Sausedo, Michael A.;Moen, Grant A.;Lee, Isaac J.;Ivan, Dominic J.;Krall, Tyler D.;Peoples, Samuel J.;Perez, Anthony;Tromba, Lucas;Le, Anh;Khadka, Iraj;Petros, Ryan;Savage, Brianna M.;Salama, Eleine;Salama, Jakline;Ziller, Joseph W.;Noh, Youngbin;Lee, Ming-Yue;Liu, Wei;Welch, John S.;Marshall, Pamela A.;Wagner, Carl E.
通讯作者：
Wagner, Carl E.