Modulate Cullin-RING E3 ubiquitin ligases by small molecule agents

通过小分子试剂调节 Cullin-RING E3 泛素连接酶

基本信息

批准号：
10200718
负责人：
Robert J DeVita
金额：
$ 70.28万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10200718
关键词：
Acute Myelocytic Leukemia Address Affinity Animals Apoptosis Area Binding Biochemical Biological Assay C-terminal CDT1 Gene CUL1 gene CUL5 gene Cancer Model Cell Line Cell division Cells Cellular Assay Chemical Structure Chemicals Complex Cullin Proteins Drug Kinetics Enzymes Exhibits FLT3 gene Family Human In Vitro Laboratories Lead Leukemic Cell Ligand Binding Ligands Ligase Malignant Neoplasms Mediating Modeling Modification Molecular Mus Mutation N-terminal Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Play Polyubiquitination Pre-Clinical Model Property Proteins RBX1 gene Reporting Ring Finger Domain Rodent Role Signal Transduction Small Interfering RNA Specificity Structure-Activity Relationship Study models Survival Rate Synthesis Chemistry Testing Therapeutic Tissues Tumor Suppression Ubiquitin Ubiquitination Variant Xenograft procedure analog anti-cancer base cancer cell cancer therapy cellular targeting chemotherapy cullin 4A cytotoxicity efficacy study high throughput screening improved in vivo inhibitor/antagonist interest leukemia leukemia treatment member mouse model novel pharmacophore receptor response scaffold small molecule small molecule inhibitor tumor ubiquitin-protein ligase

项目摘要

Project Summary Recently we have discovered a group of drug-like small molecules that inhibit Cullin-RING E3 ubiquitin ligase 4 (CRL4). We have found that these molecules are toxic to a subset of leukemia cell lines, which express very low levels of the CRL4 component cullin 4. Moreover, the CRL4 inhibitors exhibit anti-tumor activity in experimental mice. These preliminary findings suggest an interesting possibility that some low-cullin 4- expressing leukemia lines are vulnerable to our newly discovered CRL4 inhibitors and thus can be exploited for selective cancer therapies. In this project, we propose to improve CRL4 inhibitors using synthetic chemistry and to understand the molecular basis of how the small molecule compounds act to inhibit CRL4. Finally, we will develop both cell- and animal-based pre-clinical models to evaluate the anti-cancer potential for the CRL4 inhibitors against a subset of leukemia that are characterized by low cullin 4 abundance. Such information is critical for developing new strategy to improve the treatment of leukemia.

项目概要最近我们发现了一组抑制Cullin-RING E3泛素连接酶4的药物样小分子（CRL4）。我们发现这些分子对白血病细胞系的一个子集具有毒性，这些细胞系表达非常低水平的 CRL4 成分 cullin 4。此外，CRL4 抑制剂在实验小鼠。这些初步发现表明了一个有趣的可能性，即某些低剔除蛋白 4- 表达白血病细胞系易受我们新发现的 CRL4 抑制剂的影响，因此可用于选择性癌症治疗。在这个项目中，我们建议使用合成化学来改进 CRL4 抑制剂并了解小分子化合物如何抑制 CRL4 的分子基础。最后，我们将开发两种细胞- 和基于动物的临床前模型，以评估 CRL4 抑制剂针对癌症的抗癌潜力白血病的一个亚型，其特征是 cullin 4 丰度低。这些信息对于开发至关重要改善白血病治疗的新策略。