A Novel Compound for Targeted Treatment of CBF Leukemia

白血病是一种涉及发育中的白色血细胞的骨髓癌，通常与产生融合基因的特异性、复发性染色体易位和倒位相关，融合基因在白血病发生中起关键作用。 在这个项目中，基于目前对白血病如何在分子水平上发展的理解，正在为白血病的一个亚组开发靶向治疗。白血病的核心结合因子（CBF）亚组包含CBF融合基因，已被证明在白血病的发展中发挥关键作用。目前CBF白血病的治疗方法并不理想，长期生存率为50%。研究小组进行了一个小型化学库筛选，以寻找阻断CBF蛋白相互作用的抑制剂。通过生物化学，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。特别是，在小鼠CBF白血病模型的初步研究中，三种化合物之一显示出与标准化疗药物相似的白血病减少能力。研究人员将在这种小鼠模型中完成疗效研究，开发一种或多种备用化合物，优化配方，并进行药代动力学和毒理学测试，以进行临床试验。 TRND的研究人员已经成功地优化和证明了动物疾病模型的实用性。TRND科学家正在进行药物化学优化，以确定适合正式临床前开发的化合物。一旦确定了这种化合物，TRND将进行必要的研究，以支持向美国食品和药物管理局提交研究性新药申请。

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. In particular, one of the three compounds has shown leukemia reduction capability similar to standard chemotherapy drugs in preliminary studies in a mouse CBF leukemia model. The researchers will complete efficacy studies in this mouse model, develop one or more backup compounds, optimize formulation, and perform pharmacokinetics and toxicology tests that will lead to clinical trials. TRND researchers have successfully optimized and demonstrated the utility of the animal disease model. TRND scientists are performing medicinal chemistry optimization to identify a compound suitable for formal preclinical development. Once such a compound is identified, TRND will conduct the necessary studies to support filing an Investigational New Drug application with the Food and Drug Administration.