Novel Small-Molecule Probes Targeting Oncogenic Fusion MLL in Pediatric Leukemia

针对小儿白血病致癌融合 MLL 的新型小分子探针

• 批准号: 10340987
• 负责人: Yongcheng Song
• 金额: $ 43.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-10 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10340987
• 关键词: AF-9 protein; Acute; Acute Myelocytic Leukemia; Acute leukemia; Adolescent; Adult; Animals; Apoptosis; Binding; Biochemical; Biological; Biological Assay; Biological Testing; Bone Marrow; Bone Marrow Cells; C-terminal; CDK9 Protein Kinase; Cells; Chemicals; Child; Childhood; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Chromosomal translocation; Clinical; Complex; Consensus Sequence; DNA Polymerase II; DNA-Directed RNA Polymerase; Drug Kinetics; Drug Targeting; Evaluation; Event; Exhibits; Fusion Oncogene Proteins; Gene Expression; Genes; Genetic Transcription; Human; Immunomodulators; Immunoprecipitation; In Vitro; Infant; Leukemic Cell; Lymphoblastic Leukemia; MLL gene; MLLT2 gene; MLLT3 gene; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Methylation; Methyltransferase; Mixed-Lineage Leukemia; Molecular Biology; Mutagenesis; Myelogenous; N-terminal; Neonatal Leukemia; Normal Cell; Oncogenes; Oncogenic; Organ; Outcome; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Positive Transcriptional Elongation Factor B; Prognosis; Proliferating; Proteins; Roentgen Rays; Role; Sampling; Second Primary Cancers; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Transcription Elongation; Validation; X-Ray Crystallography; assay development; base; biophysical analysis; chromatin immunoprecipitation; cofactor; conventional therapy; cyclin T1; cytotoxicity; design; drug candidate; genetic signature; high throughput screening; improved; in vivo; inhibitor; leukemia; leukemia initiating cell; mouse model; novel; paralogous gene; programs; protein protein interaction; rational design; recruit; response; screening; side effect; small molecule; small molecule inhibitor; stem cells; transcription factor; tumorigenesis

Acute leukemia, including acute myeloid (AML) and lymphoid leukemia (ALL), is the most common (1 out of 3) cancer in children and adolescents. Particularly, leukemia caused by chromosome translocations involving mixed lineage leukemia (MLL) gene accounts for ~75% of leukemia in infants and ~10% in children/adults with a poor prognosis. Compared to other pediatric ALL with a 5-year survival of ~90%, that for MLL-rearranged ALL is only ~40%, and for very young infants, the survival is even <20%. MLL-rearranged AML patients have similarly poor clinical outcomes to other AMLs. Current treatments are conventional chemo-drugs, which kill all rapidly proliferating cells including normal stem cells in bone marrow and other organs. This causes severe toxicities, side effects, and even secondary cancer due to mutagenesis. There is therefore a pressing need to find less toxic drugs targeting MLL-oncogene that drives the malignancy. MLL-oncogene consists of MLL fused with another gene. AF9 (~30%) and AF4 (35%) are the most frequent fusion partners of MLL. These proteins, together with DOT1L (a known drug target for the leukemia), associate with each other and constitute the so- called super elongation complex (SEC), which causes malignant gene expression in leukemia. Previous studies show the protein-protein interactions between AF9 and AF4 or DOT1L is critical to MLL-leukemia, but is dispensable in normal cells. This project aims to find and develop the first small-molecule inhibitors that disrupt the AF9-AF4/DOT1L interaction, which could be novel chemical probes for biological studies of AF9/SEC, or potential therapeutics for MLL-rearranged leukemia with a low toxicity. The Specific Aim 1 is to use rational design and medicinal chemistry to find potent, drug-like inhibitors of AF9. Aim 2 is to perform biochemical, X-ray and NMR structural studies to characterize inhibitor-AF9 interactions. Aim 3 is to perform cell-based assays to test biological activities of selected potent inhibitors, and Aim 4 is to perform pharmacokinetics, toxicity, and antitumor activity testing to identify useful chemical probes or potential drug candidates.

急性白血病，包括急性骨髓性（AML）和淋巴性白血病（ALL），是最常见的（1/3） 儿童和青少年的癌症。特别是由染色体易位引起的白血病， 混合系白血病（MLL）基因占婴儿白血病的约75%，占儿童/成人白血病的约10%， 预后不佳与其他5年生存率约为90%的儿童ALL相比，MLL重排 ALL仅为~ 40%，对于非常年幼的婴儿，存活率甚至<20%。MLL重排的AML患者 与其他AML的临床结局相似。目前的治疗方法是常规的化学药物， 快速增殖的细胞，包括骨髓和其他器官中的正常干细胞。这导致严重的 毒性，副作用，甚至由于诱变而继发癌症。因此，迫切需要 找到毒性较小的药物，靶向导致恶性肿瘤的MLL癌基因。MLL-癌基因由MLL融合 另一个基因。AF 9（~30%）和AF 4（35%）是MLL最常见的融合伴侣。这些蛋白质， 与DOT 1 L（白血病的已知药物靶标）一起，彼此缔合并构成所述- 称为超延伸复合物（SEC），它导致白血病中的恶性基因表达。先前 研究表明，AF 9和AF 4或DOT 1 L之间的蛋白质-蛋白质相互作用对MLL-白血病至关重要，但 在正常细胞中被激活。该项目旨在寻找和开发第一个小分子抑制剂， 破坏AF 9-AF 4/DOT 1 L相互作用，这可能是生物学研究的新化学探针， AF 9/SEC或潜在的低毒性MLL重排白血病治疗剂。具体目标1是 使用合理的设计和药物化学来寻找有效的AF 9药物样抑制剂。目标二：执行 生物化学、X射线和NMR结构研究来表征β-AF 9相互作用。目标3：执行 基于细胞的测定来测试所选择的有效抑制剂的生物活性，并且目的4是进行 药代动力学、毒性和抗肿瘤活性测试，以鉴定有用的化学探针或潜在的药物 候选人