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。在小鼠CBF白血病模型的初步研究中，这些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。 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，并首次证明了初始先导化合物作为单一疗法在模型中是有效的。TRND科学家进行了药物化学优化，以确定在小鼠中重复给药后具有显著改善的药代动力学和耐受性的化合物。该合作者开发了一种新的体外疗效测定法，使用从骨髓中提取的细胞，以支持药物化学。在动物疾病模型中评估了优化的先导化合物，但其效果不如初始先导化合物。

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.