IPP/CNRS-A017: A chemical probe for human dihydroorotate dehydrogenase (hDHODH)

Current research in chemical biology Pub Date : 2022-01-01 DOI:10.1016/j.crchbi.2022.100034

Andreas Krämer , Amelie Tjaden , Benardina Ndreshkjana , Claudia Tredup , Henner F. Farin , Stefan Knapp , Yves L. Janin , Susanne Müller

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Abstract

Human Dihydroorotate dehydrogenase, which catalyses de novo pyrimidine biosynthesis, is an emerging target for treatment of infectious diseases, arthritis and cancer. In order to provide a chemical tool studying this key enzyme, we characterized IPP/CNRS-A017, a highly potent, selective, and cell-active inhibitor of the human Dihydroorotate dehydrogenase (hDHODH). In this report, we describe the crystal structure of IPP/CNRS-A017 in complex with hDHODH, providing inside into its binding mode. Additionally, further off-target profiling in a kinome-wide screen and a G-Protein-Coupled Receptors screen as well as investigated cell viability effects in three different cell lines (HEK293T, U2OS, human fibroblasts) confirmed that IPP/CNRS-A017 is a highly selective chemical tool to study the biology of hDHODH. Specific sensitivity to IPP/CNRS-A017 was observed in patient-derived colorectal cancer organoids.

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IPP/CNRS-A017:人二氢乙酸脱氢酶(hDHODH)化学探针

人二氢羟酸脱氢酶，催化新的嘧啶生物合成，是治疗传染病、关节炎和癌症的新兴靶点。为了提供研究这一关键酶的化学工具，我们对IPP/CNRS-A017进行了表征，IPP/CNRS-A017是一种高效、选择性和细胞活性的人二氢羟酸脱氢酶(hDHODH)抑制剂。在本报告中，我们描述了IPP/CNRS-A017与hDHODH配合物的晶体结构，提供了其结合模式的内部。此外，在kinomer -wide筛选和g蛋白偶联受体筛选中进一步进行脱靶分析，并研究了三种不同细胞系(HEK293T, U2OS，人成纤维细胞)的细胞活力影响，证实IPP/CNRS-A017是研究hDHODH生物学的高选择性化学工具。在患者来源的结直肠癌类器官中观察到对IPP/CNRS-A017的特异性敏感性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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