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

Identification of small molecule inhibitors of the DDI2 protease

DDI2 蛋白酶小分子抑制剂的鉴定

基本信息

批准号：
10638837
负责人：
Gary L. Kleiger
金额：
$ 73.1万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-10 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638837
关键词：
Achievement Acquired Immunodeficiency Syndrome Address Affect Apoptosis Applications Grants Area Binding Biological Assay Biophysics Cancer Patient Catalytic Domain Cell Survival Cells Cellular Assay Clinic Clinical Trials Data Detection Development Disease remission Dose Drug Targeting Dryness Enzymes Event Exhibits FDA approved Fruit Funding Future Genes Goals Grant HIV Protease Human Immune system Length Libraries Marketing Measurement Modality Multiple Myeloma Mus Normal Cell Pathway interactions Patient-Focused Outcomes Patients Peptide Hydrolases Play Powder dose form Predisposition Production Protease Inhibitor Proteasome Inhibition Proteasome Inhibitor Protein Kinase Proteins Protocols documentation Recovery Reproducibility Risk Role Signal Transduction Pathway System Testing Therapeutic Transcript Ubiquitin Up-Regulation Validation Work Xenograft Model cancer cell cancer therapy cheminformatics counterscreen expectation high throughput screening immune modulating agents inhibitor liquid chromatography mass spectrometry malignant breast neoplasm multicatalytic endopeptidase complex programs protein degradation proteostasis response scaffold scale up screening side effect small molecule inhibitor synergism targeted cancer therapy transcription factor tumor tumor growth

项目摘要

PROJECT SUMMARY Proteasome inhibitors are currently being used in the clinic against Multiple myeloma. This approach is thought to work at least in part because cancer cells appear to rely more heavily on proteasomes than do normal cells. However, our previous studies showed that proteasome inhibition invokes an adaptive program driven by the transcription factor NRF1 which upregulates proteasome genes resulting in the recovery of proteasome activity, thus limiting the efficacy of this approach. Consistent with this notion, our preliminary data suggest that depletion of NRF1 potentiates the action of proteasome inhibition therapy in a breast cancer xenograft model. Taking advantage of the fact that a protease DDI2 is essential for NRF1 activation, here we propose to identify small molecule inhibitors of this protease that could be used to enhance the efficacy of proteasome inhibitors. Moreover, based on our preliminary data that showed depleting DDI2 in itself retards tumor growth, DDI2 inhibitors could also find use as a single-agent. Based on our pilot screen that demonstrates feasibility and consistent with the goals of PAR-20-271, this 4-year project will pursue the following specific aims. In AIM 1, we will express and purify DDI2 protein and perform high-throughput screens using a protein thermal shift (PTS) assay to identify compounds that bind DDI2. In AIM 2, we will perform hit selection, confirmation and profiling using a panel of secondary assays that includes orthogonal and counter-screen assays as well as biophysical assays. In AIM 3, we will perform hit validation, hit expansion, probe selection and profile the mechanism of action of hits, followed by cellular assays to assess DDI2 target engagement, impact on the DDI2-NRF1 axis and cancer cell apoptosis.

项目总结