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.

项目概要 混合谱系白血病 (MLL) 基因重排约占人类所有基因的 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) 白血病患者对标准的反应特别差 治疗和悲观的预后。迄今为止，尚无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 甲基转移酶复合物（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 合作伙伴（例如 c-MYC）相互作用。重要的是，之间的相互作用 WDR5 及其各种结合伴侣对于维持肿瘤发生和 WDR5 的遗传耗竭至关重要 抑制 MLL-r 白血病的增殖。因此，WDR5是MLL-r有前途的药物靶点 白血病。然而，虽然小分子抑制剂可以有效阻断蛋白质-蛋白质相互作用（PPI） WDR5 及其结合伙伴之间的关系已经开发出来，这些 WDR5 PPI 抑制剂基本上无效 与 WDR5 基因的细胞杀伤作用相反，其在杀伤 MLL-r 白血病细胞方面缺乏体内功效 击倒或击倒。我们假设小分子对 WDR5 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优于 WDR5 的药理学抑制 PPI 抑制剂用于治疗 MLL-r 白血病。为了检验这个假设，我们建议发现先入为主的 使用蛋白水解靶向嵌合体 (PROTAC) 技术的 WDR5 类小分子降解剂和 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 降级器 项目不仅可以帮助我们测试我们的创新治疗假说，还可以进一步发展为 进入 MLL-r 白血病患者临床试验的候选药物。这些 WDR5 PROTAC 还 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。