A Novel Compound for Targeted Treatment of CBF Leukemia

一种靶向治疗 CBF 白血病的新型化合物

• 批准号: 10253924
• 负责人: Philip Sanderson
• 金额: $ 146.99万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10253924
• 关键词: Animal Disease Models; Animal Model; Biochemical; Biological Assay; Bone Marrow; Bone Marrow Transplantation; Cell Culture Techniques; Cell Extracts; Cessation of life; Chemicals; Chromosomal translocation; Chromosome inversion; Core-Binding Factor; Development; Dose; Drug Kinetics; Drug Targeting; Hemorrhage; In Vitro; Infection; Lead; Leukocytes; Life; Malignant Neoplasms; Modeling; Molecular; Molecular Abnormality; Mus; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Proteins; Recurrence; Research; Research Personnel; Role; Scientist; Study models; Subgroup; Survival Rate; Therapeutics for Rare and Neglected Diseases; Time; base; chemotherapy; fusion gene; improved; inhibitor/antagonist; kidney dysfunction; lead optimization; leukemia; leukemogenesis; novel; rare cancer; side effect; small molecule libraries; standard care; targeted treatment

Leukemia is a bone marrow cancer involving developing white blood cells and often is associated with specific, recurrent chromosome translocations and inversions that generate fusion genes, which play critical roles in leukemogenesis. In this project, targeted treatments are being developed for a subgroup of leukemia based on current understanding of how leukemia develops at the molecular level. The core binding factor (CBF) subgroup of leukemia contains CBF fusion genes that have been shown to play critical roles in leukemia development. Current treatments for CBF leukemia are not optimal, with long-term survival at 50 percent. The research team conducted a small chemical library screen to find inhibitors that block CBF protein interactions. Through biochemical, cell culture and animal model studies, they identified three chemically related lead compounds. One of these compounds showed leukemia reduction capability similar to standard chemotherapy drugs in preliminary studies in a mouse CBF leukemia model. TRND researchers have successfully optimized and demonstrated the utility of the animal disease model and showed for the first time that the initial lead compound is effective in the model as monotherapy. TRND scientists performed medicinal chemistry optimization to identify a compound with significantly improved pharmacokinetics and tolerability after repeat dosing in mice. The collaborator developed a new in vitro efficacy assay, using cells extracted from bone marrow, to support the medicinal chemistry. The optimized lead compound was evaluated in the animal disease model but was less effective than the initial lead.

白血病是一种骨髓癌，涉及发展白细胞，并且通常与特定的复发性染色体易位和产生融合基因的反转相关，这些基因在白血病中起着至关重要的作用。 在该项目中，基于当前对白血病在分子水平发展的方式的理解，正在为白血病亚组开发目标治疗。白血病的核心结合因子（CBF）亚组包含CBF融合基因，这些基因已证明在白血病发育中起关键作用。目前对CBF白血病的治疗不是最佳的，长期生存率为50％。研究小组进行了一个小型化学库筛选，以查找阻断CBF蛋白相互作用的抑制剂。通过生化，细胞培养和动物模型研究，他们确定了三种化学相关的铅化合物。这些化合物之一显示，在小鼠CBF白血病模型中，在初步研究中，白血病的还原能力与标准化疗药物相似。 TRND研究人员已成功优化并证明了动物疾病模型的实用性，并首次表明初始铅化合物在模型中作为单一疗法有效。 TRND科学家进行了药物化学优化，以鉴定小鼠重复给药后具有显着改善的药代动力学和耐受性的化合物。合作者使用从骨髓中提取的细胞开发了一种新的体外功效测定，以支持药物化学。在动物疾病模型中评估了优化的铅化合物，但没有初始铅的效果。