Malarz Katarzyna, Mularski Jacek, Pacholczyk Marcin, Musiol Robert
August Chełkowski Institute of Physics and Silesian Center for Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pułku Piechoty 1, 41-500 Chorzów, Poland.
Institute of Chemistry, University of Silesia in Katowice, 75 Pułku Piechoty 1A, 41-500 Chorzów, Poland.
Cancers (Basel). 2020 Feb 26;12(3):536. doi: 10.3390/cancers12030536.
Isocitrate dehydrogenases constitute a class of enzymes that are crucial for cellular metabolism. The overexpression or mutation of isocitrate dehydrogenases are often found in leukemias, glioblastomas, lung cancers, and ductal pancreatic cancer among others. Mutation R132H, which changes the functionality of an enzyme to produce mutagenic 2-hydroxyglutarate instead of a normal product, is particularly important in this field. A series of inhibitors were described for these enzymes of which ivosidenib was the first to be approved for treating leukemia and bile duct cancers in 2018. Here, we investigated the polypharmacological landscape of the activity for known sulfamoyl derivatives that are inhibitors, which are selective towards IDH1 R132H. These compounds appeared to be effective inhibitors of several non-receptor kinases at a similar level as imatinib and axitinib. The antiproliferative activity of these compounds against a panel of cancer cells was tested and is explained based on the relative expression levels of the investigated proteins. The multitargeted activity of these compounds makes them valuable agents against a wide range of cancers, regardless of the status of IDH1.
异柠檬酸脱氢酶是一类对细胞代谢至关重要的酶。异柠檬酸脱氢酶的过表达或突变常见于白血病、胶质母细胞瘤、肺癌和胰腺导管癌等。其中，将酶的功能改变以产生诱变剂2-羟基戊二酸而非正常产物的R132H突变在该领域尤为重要。针对这些酶已描述了一系列抑制剂，其中艾伏尼布于2018年率先获批用于治疗白血病和胆管癌。在此，我们研究了已知的作为抑制剂的氨磺酰衍生物对IDH1 R132H具有选择性的活性的多药理学情况。这些化合物似乎是几种非受体激酶的有效抑制剂，其效力与伊马替尼和阿昔替尼相当。测试了这些化合物对一组癌细胞的抗增殖活性，并根据所研究蛋白质的相对表达水平进行了解释。这些化合物的多靶点活性使其成为针对多种癌症的有价值药物，无论IDH1状态如何。
