Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
Eur J Med Chem. 2023 Oct 5;258:115509. doi: 10.1016/j.ejmech.2023.115509. Epub 2023 May 26.
Acute myeloid leukaemia (AML) is an aggressive type of leukaemia with low rates of long-term survival. While the current standard of care is based on cytotoxic chemotherapy, a promising emerging approach is differentiation therapy. However, most current differentiating agents target specific mutations and are effective only in certain patient subtypes. To identify agents which may be effective in wider population cohorts, we performed a phenotypic screen with the myeloid marker CD11b and identified a compound series that was able to differentiate AML cell lines in vitro regardless of their mutation status. Structure-activity relationship studies revealed that replacing the formamide and catechol methyl ether groups with sulfonamide and indazole respectively improved the in vitro metabolic profile of the series while maintaining the differentiation profile in multiple cell lines. This optimisation exercise enabled progression of a lead compound to in vivo efficacy testing. Our work supports the promise of phenotypic screening to identify novel small molecules that induce differentiation in a wide range of AML subtypes.
急性髓细胞白血病（AML）是一种侵袭性白血病，其长期生存率较低。虽然目前的治疗标准基于细胞毒性化疗，但一种有前途的新兴方法是分化疗法。然而，大多数当前的分化剂针对特定的突变，仅在某些患者亚型中有效。为了确定可能对更广泛的人群有效 的药物，我们使用髓样标志物 CD11b 进行了表型筛选，并发现了一系列化合物，这些化合物能够在体外分化 AML 细胞系，而不论其突变状态如何。构效关系研究表明，用磺酰胺和吲唑分别替代甲酰胺和儿茶酚甲基醚基团，在保持多种细胞系分化谱的同时，改善了该系列的体外代谢谱。这项优化工作使先导化合物能够进行体内疗效测试。我们的工作支持表型筛选来识别新型小分子的承诺，这些小分子可诱导广泛的 AML 亚型分化。
