Röhrig Ute F, Majjigapu Somi Reddy, Caldelari Daniela, Dilek Nahzli, Reichenbach Patrick, Ascencao Kelly, Irving Melita, Coukos George, Vogel Pierre, Zoete Vincent, Michielin Olivier
Molecular Modeling Group, SIB Swiss Institute for Bioinformatics, CH-1015 Lausanne, Switzerland.
Molecular Modeling Group, SIB Swiss Institute for Bioinformatics, CH-1015 Lausanne, Switzerland; Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
Bioorg Med Chem Lett. 2016 Sep 1;26(17):4330-3. doi: 10.1016/j.bmcl.2016.07.031. Epub 2016 Jul 16.
Indoleamine 2,3-dioxygenase 2 (IDO2) is a potential therapeutic target for the treatment of diseases that involve immune escape such as cancer. In contrast to IDO1, only a very limited number of inhibitors have been described for IDO2 due to inherent difficulties in expressing and purifying a functionally active, soluble form of the enzyme. Starting from our previously discovered highly efficient 4-aryl-1,2,3-triazole IDO1 inhibitor scaffold, we used computational structure-based methods to design inhibitors of IDO2 which we then tested in cellular assays. Our approach yielded low molecular weight inhibitors of IDO2, the most active displaying an IC50 value of 51μM for mIDO2, and twofold selectivity over hIDO1. These compounds could be useful as molecular probes to investigate the biological role of IDO2, and could inspire the design of new IDO2 inhibitors.
吲哚胺2,3-双加氧酶2（IDO2）是治疗涉及免疫逃逸的疾病（如癌症）的潜在治疗靶点。与IDO1不同，由于在表达和纯化功能活性、可溶形式的该酶时存在固有困难，针对IDO2的抑制剂仅有非常有限的报道。从我们之前发现的高效4-芳基-1,2,3-三唑IDO1抑制剂支架出发，我们使用基于结构的计算方法设计IDO2抑制剂，然后在细胞试验中进行测试。我们的方法得到了IDO2的低分子量抑制剂，其中活性最高的对mIDO2的IC50值为51μM，对hIDO1具有两倍的选择性。这些化合物可用作研究IDO2生物学作用的分子探针，并可为新型IDO2抑制剂的设计提供灵感。
