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: 10539338
• 负责人: Yongcheng Song
• 金额: $ 42.88万
• 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/10539338
• 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; Cell Proliferation; Cells; Chemicals; Child; Childhood; Childhood Leukemia; Chromosomal translocation; Clinical; Complex; Consensus Sequence; 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; Myeloid Leukemia; N-terminal; Neonatal Leukemia; Normal Cell; Oncogenes; Oncogenic; Organ; Outcome; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphorylation; Play; Polymerase; Positive Transcriptional Elongation Factor B; Prognosis; Proliferating; Proteins; RNA Polymerase II; Roentgen Rays; Role; Sampling; Second Primary Cancers; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Transcription Elongation; Validation; X-Ray Crystallography; assay development; 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; leukemic transformation; mixed lineage leukemia cell; mouse model; novel; paralogous gene; pediatric acute leukemia; programs; protein protein interaction; rational design; recruit; response; screening; side effect; small molecule; small molecule inhibitor; stem cells; transcription factor; tumor; 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，包括急性髓样（AML）和淋巴性白血病（ALL），是最常见的（3中的1个） 儿童和青少年的癌症。特别是，由染色体易位引起的白血病涉及 混合谱系白血病（MLL）基因占婴儿白血病的约75％，儿童/成人占10％ 预后不佳。与其他儿科相比，全部5年生存率约为90％ 一切只有〜40％，对于非常年轻的婴儿，生存率甚至<20％。 MLL重新培养的AML患者具有 同样，其他AML的临床结果差。当前治疗是常规的化学药物，杀死所有 快速增殖的细胞，包括骨髓和其他器官中的正常干细胞。这会导致严重 由于诱变引起的毒性，副作用，甚至是继发性癌症。因此，有迫切需要 找到针对驱动恶性肿瘤的MLL-癌基因的毒性较少。 MLL-癌基因由MLL融合组成 与另一个基因。 AF9（〜30％）和AF4（35％）是MLL最常见的融合伙伴。这些蛋白质， 与dot1l（白血病的已知药物靶标）一起，彼此相关并构成So- 称为超级伸长复合物（SEC），该复合物在白血病中引起恶性基因表达。以前的 研究表明，AF9和AF4或DOT1L之间的蛋白质 - 蛋白质相互作用对于MLL-白血病至关重要，但是 在正常细胞中是可分配的。该项目旨在寻找和开发第一个小分子抑制剂 破坏AF9-AF4/DOT1L相互作用，这可能是用于生物学研究的新型化学探针 AF9/sec，或针对低毒性的MLL重新培养性白血病的潜在疗法。具体目的1是 使用有理设计和药物化学来发现AF9的有效的药物样抑制剂。目标2是表演 生化，X射线和NMR结构研究以表征抑制剂-AF9相互作用。目标3是表演 基于细胞的测定测试选定有效抑制剂的生物学活性，AIM 4是执行 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药物 候选人。