Identification of an IDO1 inhibitor prodrug that specifically targets tumor tissue
10.16438/j.0513-4870.2020-0016
- VernacularTitle:特异性靶向肿瘤组织的IDO1抑制剂前药的研究
- Author:
Hao FENG
1
;
Qian-qian DU
2
;
Zhi-qiang FENG
2
;
Yan LI
2
;
Zhong-cheng LIU
1
;
Xiao-ling XU
3
Author Information
1. College of Pharmacy, Hebei University, Baoding 071002, China
2. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
3. Heze Municipal Hospital, Heze 274000, China
- Publication Type:Research Article
- Keywords:
immunotherapy;
IDO inhibitor;
prodrug;
hypoxia
- From:
Acta Pharmaceutica Sinica
2020;55(5):958-966
- CountryChina
- Language:Chinese
-
Abstract:
Hypoxia-activated prodrugs that specifically target tumor tissues were designed by attaching the nitro-aromatic ring carrier molecules that can be degraded in the hypoxic microenvironment of the tumor to the hydroxyamidine group of IDO1 inhibitor compound B and epacadostat. Eleven prodrug compounds were synthesized and their structures were confirmed by 1H NMR and HR-MS. Compounds F-1 and F-6, which had a higher stability and drug release rate, were identified by an in vitro stability assay, nitroreductase reduction assay, MTT assay, and an in vivo tumor tissue hypoxia degradation assay, and then evaluated for anti-tumor efficacy in vivo. The results showed that prodrug F-1 inhibited tumor growth by 67.41%, which was significantly higher than 42.31% for the starting drug group. It appeared that the inhibition of IDO1 in the tumor tissue was different from the overall inhibition of IDO1 in vivo. Animal treatment procedures were carried out with the approval of the Animal Care and Use Committee of the Chinese Academy of Medical Sciences and Peking Union Medical College.
