Discovery of IDO1 and DNA dual targeting antitumor agents

作者：Fang, Kun; Wu, Shanchao; Dong, Guoqiang; Wu, Ying; Chen, Shuqiang; Liu, Jianhe^*; Wang, Wei^*; Sheng, Chunquan^*

来源：Organic and Biomolecular Chemistry, 2017, 15(47): 9992-9995.

DOI：10.1039/c7ob02529g

• INDOLEAMINE 2,3-DIOXYGENASE INHIBITORS
• TRYPTOPHAN CATABOLISM
• CELL PROLIFERATION
• T-CELLS
• CANCER
• CHEMOTHERAPY
• IMMUNOTHERAPY
• DERIVATIVES
• EXPRESSION
• BIOLOGY

The development of small molecules for cancer immunotherapy is highly challenging and indoleamine 2,3-dioxygenase 1 (IDO1) represents a promising target. Inspired by the synergistic effects between IDO1 inhibitors and traditional antitumor chemotherapeutics, the first orally active dual IDO1 and DNA targeting agents were designed by the pharmacophore fusion strategy. The bifunctional hybrids exhibited enhanced IDO1 enzyme inhibitory activity and in vitro cytotoxicity as compared to IDO1 inhibitor 1-methyl-tryptophan and DNA alkylating agent melphalan. In a murine LLC tumor model, the dual targeting agents demonstrated excellent antitumor efficacy, highlighting the advantages of this novel design strategy to improve the efficacy of small molecule cancer immunotherapy.

• 出版日期2017-12-21
• 单位中国人民解放军第二军医大学; 上海交通大学; 华东理工大学