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: 10615610
• 负责人: Jian Jin
• 金额: $ 64.13万
• 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/10615610
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Apoptosis; Assessment tool; Binding; Biological Assay; Biophysics; Cell Cycle Progression; Cell Proliferation; Cell model; Cells; Chemicals; Childhood Leukemia; Chromatin; Clinic; Clinical Trials; Complex; 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; Prognosis; Proliferating; Property; Protac; Public Health; Reporting; Research; Resolution; Structure; Technology; Tertiary Protein Structure; Testing; Therapeutic; Toxic effect; Translating; Xenograft procedure; antitumor effect; biophysical properties; c-myc Genes; cell killing; design; drug candidate; efficacy evaluation; histone methyltransferase; improved; in vivo; inhibitor; innovation; knock-down; leukemia; mouse model; novel therapeutic intervention; patient derived xenograft model; pharmacologic; programs; protein degradation; protein protein interaction; recruit; response; small molecule; small molecule inhibitor; standard care; targeted treatment; therapeutic target; 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 混合细胞白血病（MLL）基因的重排约占所有人类的10％ 白血病。这种重排在小儿白血病中更为常见。最多80％的婴儿急性 淋巴细胞白血病（全）和35-50％的婴儿急性髓样白血病（AML）的特征是MLL 重排。 MLL重新培训（MLL-R）白血病患者对标准的反应特别差 治疗和惨淡的预后。迄今为止，尚未批准有效的靶向疗法治疗 这些致命的癌症。 WD40重复域蛋白5（WDR5）是MLL1组蛋白的必不可少的亚基 甲基转移酶复合酶（MLL1复合物），对于MLL1复合物介导的基因调节至关重要 转录。 WDR5还与非MLL伴侣（例如C-MYC）互动。重要的是，之间的相互作用 WDR5及其各种结合伙伴对于维持肿瘤发生和WDR5的遗传耗竭至关重要 抑制MLL-R白血病的扩散。因此，WDR5是MLL-R的有前途的药物靶标 白血病。但是，尽管有效阻断蛋白质蛋白质相互作用（PPI）的小分子抑制剂（PPI） 在WDR5及其结合伙伴之间，这些WDR5 PPI抑制剂在很大程度上无效 在杀死MLL-R白血病细胞和缺乏体内功效时，与WDR5遗传的细胞杀死作用相反 淘汰或敲除。我们假设小分子对WDR5的药理降解 作为一种新型的治疗策略，降级者将有效，并且优于WDR5的药理抑制 通过PPI抑制剂治疗MLL-R白血病。为了检验这一假设，我们建议发现第一 使用蛋白水解靶向嵌合体（Protac）技术和 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前途的初步 结果，表明拟议的研究是可行的。在此产生的WDR5 Protac降解器 项目不仅可以帮助我们检验我们的创新治疗假设，而且还可以进一步发展为 候选药物候选人与MLL-R白血病患者进行临床试验。这些WDR5 Protac也是 评估其他癌症中WDR5降解的治疗潜力的有价值的化学探针。