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.

项目总结 混合系白血病(MLL)基因重排约占人类总数的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 淋巴母细胞性白血病(ALL)和35-50%的婴儿急性髓系白血病(AML)以MLL为特征 重新安排。MLL重排(MLL-r)白血病患者对标准的反应特别差 治疗和令人沮丧的预后。迄今为止，还没有有效的靶向疗法被批准用于治疗。 这些致命的癌症。WD40重复结构域蛋白5(WDR5)是MLL1组蛋白的重要亚基 甲基转移酶复合体(MLL1复合体)，对MLL1复合体介导的基因调控至关重要 抄写。WDR5还与c-myc等非MLL合作伙伴互动。重要的是， WDR5和它的各种结合伙伴对于维持肿瘤发生和WDR5的基因缺失是必不可少的 抑制MLL-r白血病的增殖。因此，WDR5是一种很有前途的MLL-r药物靶点。 白血病。然而，尽管有效阻断蛋白质-蛋白质相互作用(PPI)的小分子抑制剂 在WDR5及其结合伙伴之间已经开发出，这些WDR5 PPI抑制剂在很大程度上是无效的 在杀伤MLL-r白血病细胞方面缺乏体内药效，与WDR5基因的细胞杀伤作用相反 击倒或击倒。我们假设WDR5是通过小分子药物降解的 降解剂作为一种新的治疗策略将是有效的，并优于WDR5的药物抑制 PPI抑制剂用于治疗MLL-r白血病。为了检验这一假设，我们建议发现- 使用蛋白水解靶向嵌合体(PROTAC)技术的WDR5类小分子降解剂 在MLL-r白血病细胞和小鼠模型中对它们进行评估。我们已经产生了非常有希望的初步结果 结果表明，所提出的研究是可行的。在此生成的WDR5 PROTAC降解器 该项目不仅将帮助我们测试我们的创新治疗假说，而且还可以进一步发展成为 进入MLL-r白血病患者临床试验的候选药物。这些WDR5 PROTAC也是 用于评估WDR5降解在其他癌症中的治疗潜力的有价值的化学探针。