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Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias

发现一流的 WDR5 PROTAC 作为 MLL 重排白血病的新型治疗策略

基本信息

批准号：
10387368
负责人：
Jian Jin
金额：
$ 67.16万
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：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10387368
关键词：
Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Apoptosis Binding Biological Assay Biophysics Cell Cycle Progression Cell Proliferation Cell model Cells Chemicals Childhood Leukemia Chromatin Clinic Clinical Trials Complex Crystallization Disease Dose Drug Kinetics Drug Targeting Future Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Growth Human In Vitro Infant Knock-out Lead Leukemic Cell Ligands Link MLL gene Malignant Neoplasms Mediating Mixed-Lineage Leukemia Oncogenic Oncoproteins Patients Pharmacology Prognosis Property Protac Public Health Reporting Research Resolution Structure Technology Tertiary Protein Structure Testing Therapeutic Toxic effect Translating Xenograft procedure antitumor effect base biophysical properties c-myc Genes cell killing design drug candidate histone methyltransferase improved in vivo inhibitor innovation knock-down leukemia mouse model novel therapeutic intervention patient derived xenograft model programs protein degradation protein protein interaction recruit response small molecule small molecule inhibitor standard care targeted treatment therapeutic target tool transcriptome treatment strategy tumor growth tumorigenesis ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Rearrangements of the mixed-lineage leukemia (MLL) gene account for approximately 10% of all human leukemias. Such rearrangements are more common in pediatric leukemias. Up to 80% of infant acute lymphoblastic leukemias (ALL) and 35-50% of infant acute myeloid leukemias (AML) are characterized by MLL rearrangements. MLL-rearranged (MLL-r) leukemia patients have particularly poor response to standard treatments and a dismal prognosis. To date, no effective targeted therapies have been approved for treating these deadly cancers. WD40 repeat domain protein 5 (WDR5) is an essential subunit of the MLL1 histone methyltransferase complex (MLL1 complex) and is crucial for MLL1 complex-mediated regulations of gene transcription. WDR5 also interacts with non-MLL partners such as c-MYC. Importantly, interactions between WDR5 and its various binding partners are essential for sustaining oncogenesis, and genetic depletion of WDR5 suppresses the proliferation of MLL-r leukemias. Therefore, WDR5 is a promising drug target for MLL-r leukemias. However, while small-molecule inhibitors that effectively block the protein-protein interactions (PPI) between WDR5 and its binding partners have been developed, these WDR5 PPI inhibitors are largely ineffective in killing MLL-r leukemia cells and lack in vivo efficacy, as opposed to the cell killing effect of WDR5 genetic knockout or knockdown. We hypothesize that pharmacological degradation of WDR5 by small-molecule degraders as a novel therapeutic strategy will be effective and superior to pharmacological inhibition of WDR5 by PPI inhibitors for the treatment of MLL-r leukemias. To test this hypothesis, we propose to discover first-in- class WDR5 small-molecule degraders using the proteolysis targeting chimera (PROTAC) technology and evaluate them in MLL-r leukemia cellular and mouse models. We have generated very promising preliminary results, suggesting that the proposed research is feasible. The WDR5 PROTAC degraders generated in this project will not only help us test our innovative therapeutic hypothesis, but can also be developed further into a drug candidate for advancing to clinical trials with MLL-r leukemia patients. These WDR5 PROTACs are also valuable chemical probes for assessing the therapeutic potential of WDR5 degradation in other cancers.

项目总结