Development of Novel PROTACs Targeting the ENL YEATS Domain for Treating MLL-rearranged Leukemias

开发针对 ENL YEATS 结构域的新型 PROTAC，用于治疗 MLL 重排白血病

基本信息

批准号：
10222062
负责人：
Jian Jin
金额：
$ 53.17万
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：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10222062
关键词：
Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Apoptosis Biochemical Biological Assay Biophysics Cell Membrane Permeability Cell Proliferation Cell model Cells Chemicals Childhood Leukemia Chromatin Chromosomal translocation Clinic Complex Development Disease Drug Kinetics Drug Targeting ENL Protein Evolution Excretory function Future Gene Expression Gene Rearrangement Growth Histone Acetylation Histone H3 Histones Human In Vitro Infant Knock-out Lead Leukemic Cell Ligands Link Lysine MLL gene MLLT3 gene Metabolism Methylation Methyltransferase Mixed-Lineage Leukemia Molecular Nature Oncogenic Pathogenesis Pathway interactions Patients Pharmacology Phenocopy Prognosis Property Protac Public Health Reader Reporting Research Technology Testing Therapeutic Toxic effect Translating absorption base cell killing design driver mutation drug candidate effective therapy gene translocation histone methyltransferase in vivo inhibitor/antagonist innovation leukemia mouse model novel novel therapeutic intervention protein degradation prototype response small molecule small molecule inhibitor standard care therapeutic target therapeutically effective transcriptome ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY The mixed-lineage leukemia (MLL) gene rearrangements account for approximately 80% of infant acute lymphoblastic leukemia (ALL) and 35-50% of infant acute myeloid leukemia (AML). Patients bearing rearrangements of the MLL gene are associated with dismal prognosis. To date, no effective therapies have been approved for treating the fatal diseases. Molecularly, inter-chromosomal translocations of MLL lead to in frame fusions of the N-terminus of MLL to the C-terminus of various fusion partners, which are known as the “driver” lesions of the diseases. Among more than 70 MLL fusion partners, a small subset of fusions account for most leukemogenic cases. In ALL, over 90% MLL rearrangements involve only four fusion partners: AFF1, AF9, ENL, and AF10, all of which are components of the super elongation complex (SEC) or the complex of the histone H3K79 methyltransferase DOT1L. It is believed that these MLL fusions share a common pathway by hijacking the SEC or DOT1L complex to promote aberrant activation of the target genes of MLL fusions, leading to the pathogenesis of leukemias. We and others have recently demonstrated that ENL, a component of the SEC and DOT1L complex, is critical for the oncogenic function of the MLL-fusions. ENL contains an evolutionally conserved YEATS domain that we identified as a reader of histone acetylation. We also found that the YEATS domain of ENL, but not AF9, is essential for growth and survival of the MLL-rearranged leukemic cells. These key findings strongly suggest that ENL is a promising therapeutic target for MLL-rearranged leukemias. However, while a recently reported small-molecule inhibitor effectively blocks the interactions between the YEATS domain of ENL/AF9 and acetylated histone H3, this ENL inhibitor has little or no effect on killing ENL-dependent MLL- rearranged leukemia cells, failing to phenocopy the cell killing effect of ENL knockout. We hypothesize that pharmacological degradation of ENL, instead of ENL inhibition that relies on occupancy-driven pharmacology, will provide a novel and effective therapeutic strategy for treating MLL-rearranged leukemias. To test this hypothesis, we propose to develop first-in-class ENL small-molecule degraders as in vivo chemical probes using the proteolysis targeting chimera (PROTAC) technology and evaluate them in MLL-rearranged leukemia cells and mouse models. We have generated promising preliminary results, suggesting that the proposed research is feasible. The ENL degrader in vivo chemical probes generated in this project will not only help us test and validate our therapeutic hypothesis, but can also be further optimized into drug candidates in the future and ultimately translated in the clinic for MLL-rearranged leukemia patients.

项目摘要混合细胞性白血病（MLL）基因重排约占婴儿急性的80％淋巴细胞白血病（全）和35-50％的婴儿急性髓样白血病（AML）。患者携带 MLL基因的重排与沮丧的预后有关。迄今为止，没有有效的疗法被批准治疗致命疾病。 MLL的分子，染色体易位导致 MLL的N末端与各种融合伙伴的C端的框架融合，这些融合被称为疾病的“驱动程序”病变。在70多个MLL融合伙伴中大多数白血病病例。总共90％以上的MLL重排仅涉及四个融合伙伴：AFF1，AF9， ENL和AF10，所有这些都是超级伸长络合物（SEC）的组成部分或 Hisstone H3K79甲基转移酶dot1l。据信这些MLL融合共享一个共同的途径劫持SEC或DOT1L复合物以促进MLL融合的靶基因异常激活白血病的发病机理。我们和其他人最近证明了ENL， SEC和DOT1L复合物对于MLL融合的致癌功能至关重要。 ENL在进化上包含我们确定为组蛋白乙酰化的读取器的保守Yeats结构域。我们还发现叶芝 ENL的结构域（而不是AF9）对于MLL rearRangeRanged白血病细胞的生长和存活至关重要。这些主要发现强烈表明，ENL是MLL重新培养白血病的有前途的治疗靶标。然而，虽然最近报道的小分子抑制剂有效地阻止了叶芝域之间的相互作用 ENL/AF9和乙酰化组蛋白H3的ENR抑制剂几乎没有影响杀死ENL依赖性的MLL- 重新排列的白血病细胞，未能表现出ENL基因敲除的细胞杀死作用。我们假设这一点 ENL的药理降解，而不是依赖于占用驱动的药理学的ENL抑制作用，而是将提供一种新颖有效的理论策略来治疗MLL重新培养的白血病。测试这个假设，我们建议使用使用体内化学问题来开发一流的ENL小分子降解器靶向嵌合体（Protac）技术的蛋白水解，并在MLL重新生长的白血病细胞中评估它们和鼠标模型。我们已经产生了承诺的初步结果，这表明拟议的研究是可行的。该项目中产生的ENL DEGRADER在体内化学问题不仅会帮助我们测试和验证我们的治疗假设，但也可以将来进一步优化为候选药物在诊所中翻译成MLL重新培养的白血病患者。