Lead optimisation of OXS007417: in vivo PK profile and hERG liability modulation to optimise a small molecule differentiation agent for the potential treatment of acute myeloid leukaemia†

IF 4.1 4区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY RSC medicinal chemistry Pub Date : 2024-07-22 DOI:10.1039/D4MD00275J

Thomas J. Cogswell, Laia Josa-Culleré, David Zimmer, Sébastien R. G. Galan, Morgan Jay-Smith, Kate S. Harris, Carole J. R. Bataille, Thomas R. Jackson, Douzi Zhang, Stephen G. Davies, Paresh Vyas, Thomas A. Milne, Graham M. Wynne and Angela J. Russell

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Abstract

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 in vivo. 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 in vivo model using HL-60 cells.

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OXS007417的先导优化：体内PK谱和hERG责任调节，以优化潜在治疗急性髓性白血病的小分子分化剂。

针对急性髓细胞性白血病开发一种安全、有效且广泛适用的分化疗法，将极大地改善全球许多患者的治疗前景。为此，我们实验室发现了一类分化药物，它们在体内小鼠模型中表现出肿瘤消退。在此，我们报告了围绕化合物 OXS007417 的先导优化过程，该过程提高了该化合物类的效力、溶解度、代谢稳定性和脱靶毒性。通过在化合物的关键位置添加氮原子，研究并成功缓解了 hERG 负性。与 OXS007417 相比，OXS008255 和 OXS008474 改善了小鼠的 PK 谱，并在使用 HL-60 细胞的皮下体内模型中延缓了肿瘤的生长。

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