Cogswell Thomas J, Josa-Culleré Laia, Zimmer David, Galan Sébastien R G, Jay-Smith Morgan, Harris Kate S, Bataille Carole J R, Jackson Thomas R, Zhang Douzi, Davies Stephen G, Vyas Paresh, Milne Thomas A, Wynne Graham M, Russell Angela J
Department of Chemistry, Chemistry Research Laboratory, University of Oxford Mansfield Road Oxford OX1 3TA UK
Department of Pharmacology, University of Oxford Mansfield Road Oxford OX1 3QT UK.
RSC Med Chem. 2024 Jul 22;15(10):3495-506. doi: 10.1039/d4md00275j.
The development of a safe, efficacious, and widely effective differentiation therapy for AML would dramatically improve the outlook for many patients worldwide. To this aim, our laboratory has discovered a class of differentiation agents that demonstrate tumour regression in murine models . Herein, we report a lead optimisation process around compound OXS007417, which led to improved potency, solubility, metabolic stability, and off-target toxicity of this compound class. A hERG liability was investigated and successfully alleviated through addition of nitrogen atoms into key positions of the compound. OXS008255 and OXS008474 demonstrated an improved murine PK profile in respect to OXS007417 and a delay in tumour growth in a subcutaneous model using HL-60 cells.
开发一种安全、有效且广泛有效的急性髓系白血病（AML）分化疗法将极大地改善全球许多患者的预后。为此，我们实验室发现了一类在小鼠模型中能使肿瘤消退的分化剂。在此，我们报告了围绕化合物OXS007417的先导化合物优化过程，该过程提高了这类化合物的效力、溶解度、代谢稳定性和脱靶毒性。研究了人醚 - 去极化激活的钾离子通道（hERG）相关风险，并通过在化合物的关键位置引入氮原子成功缓解了该风险。与OXS007417相比，OXS008255和OXS008474在小鼠体内表现出改善的药代动力学特征，并且在使用HL - 60细胞的皮下模型中延缓了肿瘤生长。
