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

• 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
• 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

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.

项目摘要 混合系白血病（MLL）基因重排约占所有人类白血病的10%。 白血病这种重排在儿童白血病中更为常见。高达80%的婴儿急性 淋巴母细胞白血病（ALL）和35-50%的婴儿急性髓细胞白血病（AML）的特征是MLL 重新安排MLL重排（MLL-r）白血病患者对标准化疗的反应特别差。 治疗和令人沮丧的预后到目前为止，还没有有效的靶向治疗被批准用于治疗 这些致命的癌症WD 40重复结构域蛋白5（WDR 5）是MLL 1组蛋白的一个必需亚基 甲基转移酶复合物（MLL 1复合物），并对MLL 1复合物介导的基因调控至关重要 转录。WDR 5还与非MLL伙伴如c-MYC相互作用。重要的是， WDR 5及其各种结合配偶体对于维持肿瘤发生和WDR 5的遗传缺失至关重要 抑制MLL-r白血病的增殖。因此，WDR 5是MLL-r的有希望的药物靶点 白血病然而，虽然小分子抑制剂，有效地阻止蛋白质-蛋白质相互作用（PPI）， 已经开发了WDR 5及其结合伴侣之间的联系，这些WDR 5 PPI抑制剂在很大程度上是无效的 与WDR 5基因的细胞杀伤作用相反， 击倒或击倒。我们假设小分子药物对WDR 5的药理学降解 降解剂作为一种新的治疗策略将是有效的，并且上级于药物抑制WDR 5 PPI抑制剂用于治疗MLL-r白血病。为了验证这一假设，我们建议先发现 使用蛋白水解靶向嵌合体（PROTAC）技术的WDR 5类小分子降解剂， 在MLL-r白血病细胞和小鼠模型中评估它们。我们已经产生了非常有希望的初步 结果表明，该研究是可行的。此次生成的WDR 5 PROTAC降解剂 该项目不仅将帮助我们测试我们的创新治疗假设，而且还可以进一步发展成为一个 用于MLL-r白血病患者临床试验的候选药物。这些WDR 5 PROTAC还 有价值的化学探针，用于评估WDR 5降解在其他癌症中的治疗潜力。