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

• 批准号: 10668982
• 负责人: Robert J DeVita
• 金额: $ 68.87万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/10668982
• 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; Collaborations; 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; 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; cancer cell; cancer therapy; cellular targeting; chemotherapy; cullin 4A; cytotoxicity; efficacy study; high throughput screening; improved; in vivo; inhibitor; interest; leukemia; leukemia treatment; member; mouse model; novel; pharmacologic; pharmacophore; receptor; response; scaffold; small molecule; small molecule inhibitor; tumor; ubiquitin-protein ligase

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.

项目总结

项目成果

Targeting Cullin-RING E3 Ubiquitin Ligase 4 by Small Molecule Modulators.

• DOI: 10.33696/signaling.2.051
• 发表时间: 2021
• 期刊: Journal of cellular signaling
• 作者: Wu K;Hopkins BD;Sanchez R;DeVita RJ;Pan ZQ
• 通讯作者: Pan ZQ

A Novel Strategy to Track Lysine-48 Ubiquitination by Fluorescence Resonance Energy Transfer.

• DOI: 10.1007/978-1-0716-1217-0_7
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Wu K;Pan ZQ
• 通讯作者: Pan ZQ

A new FRET-based platform to track substrate ubiquitination by fluorescence.

• DOI: 10.1074/jbc.ra120.016858
• 发表时间: 2021-01
• 期刊: The Journal of biological chemistry
• 作者: Wu K;Ching K;Chong RA;Pan ZQ
• 通讯作者: Pan ZQ

Cullin-RING E3 Ubiquitin Ligase 7 in Growth Control and Cancer.

Cullin环E3泛素连接酶7在生长控制和癌症中。

• DOI: 10.1007/978-981-15-1025-0_17
• 发表时间: 2020
• 期刊: Advances in experimental medicine and biology
• 作者: Pan ZQ

Monoubiquitination empowers ubiquitin chain elongation.

单泛素化可促进泛素链延伸。

• DOI: 10.1016/j.jbc.2024.105753
• 发表时间: 2024
• 期刊: The Journal of biological chemistry
• 作者: Wu,Kenneth;DeVita,RobertJ;Pan,Zhen-Qiang
• 通讯作者: Pan,Zhen-Qiang