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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：
10616478
负责人：
Jian Jin
金额：
$ 50.31万
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/10616478
关键词：
Acetylation 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 Proliferating Property Protac Public Health Reader Reporting Research Technology Testing Therapeutic Toxic effect Translating absorption cell killing design driver mutation drug candidate effective therapy efficacy evaluation gene translocation histone methyltransferase in vivo inhibitor innovation leukemia mouse model novel novel therapeutic intervention pharmacologic 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.

项目摘要混合系白血病（MLL）基因重排约占婴儿急性白血病的80%。淋巴母细胞白血病（ALL）和35-50%的婴儿急性髓细胞白血病（AML）。患者轴承 MLL基因重排与预后不良有关。到目前为止，没有有效的治疗方法被批准用于治疗致命疾病。在分子水平上，MLL的染色体间易位导致了 MLL的N-末端与各种融合配偶体的C-末端的框融合，其被称为 “司机”病变的疾病。在超过70个MLL融合伴侣中，一小部分融合占了大多数白血病病例在ALL中，超过90%的MLL重排仅涉及四种融合伴侣：AFF 1，AF 9， ENL和AF 10，所有这些都是超延伸复合物（SEC）的组分，或组蛋白H3 K79甲基转移酶DOT 1 L。据信，这些MLL融合体通过以下途径共享共同的途径：劫持SEC或DOT 1 L复合物以促进MLL融合物的靶基因的异常激活，白血病的发病机制我们和其他人最近证明，ENL是 SEC和DOT 1 L复合物对于MLL融合体的致癌功能至关重要。ENL包含一个进化的保守的YEATS结构域，我们确定为组蛋白乙酰化的读者。我们还发现叶慈夫妇 ENL的结构域，而不是AF 9，是MLL重排的白血病细胞的生长和存活所必需的。这些关键的发现有力地表明ENL是MLL重排白血病的有希望的治疗靶点。然而，在这方面，而最近报道的小分子抑制剂有效地阻断了YEATS结构域之间的相互作用， ENL/AF 9和乙酰化组蛋白H3的抑制剂，这种ENL抑制剂对杀死ENL依赖性MLL的作用很小或没有作用。重排的白血病细胞，未能表型复制ENL敲除的细胞杀伤作用。我们假设 ENL的药理学降解，而不是依赖于占用驱动的药理学的ENL抑制，将为治疗MLL重排白血病提供一种新的有效的治疗策略。为了验证这一假设，我们建议开发一流的ENL小分子降解剂作为体内化学探针，蛋白水解靶向嵌合体（PROTAC）技术，并在MLL重排白血病细胞中进行评价和小鼠模型。我们已经产生了有希望的初步结果，表明拟议的研究是可行本项目中生成的ENL降解剂体内化学探针不仅有助于我们测试和验证我们的治疗假设，但也可以在未来进一步优化为候选药物，在临床上用于MLL重排的白血病患者。