A Novel Compound for Targeted Treatment of CBF Leukemia

白血病是一种涉及发育中的白细胞的骨髓癌，通常与产生融合基因的特定的、反复发生的染色体易位和倒置有关，而融合基因在白血病的发生中起着关键作用。 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，正在开发针对白血病亚群的靶向治疗。白血病的核心结合因子(CBF)亚群包含CBF融合基因，这些融合基因已被证明在白血病的发生发展中发挥关键作用。目前治疗CBF白血病的方法并不理想，长期存活率为50%。研究小组进行了一次小型化学图书馆筛选，以寻找阻止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上相关的先导化合物。特别是，在小鼠CBF白血病模型的初步研究中，三种化合物中的一种显示了类似于标准化疗药物的降低白血病能力。研究人员将在这一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，这些测试将导致临床试验。 TRND的研究人员已经成功地优化并展示了动物疾病模型的实用性。TRND的科学家们正在进行药物化学优化，以确定一种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，以支持向食品和药物管理局提交调查性新药申请。

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.