Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Bioorg Chem. 2021 May;110:104815. doi: 10.1016/j.bioorg.2021.104815. Epub 2021 Mar 10.
Cancer immunotherapy has become an emerging driving force in the development of innovative strategies to fight against cancer. Despite the significant clinical benefits that many cancer patients have gained, the generally average response rate of ~ 20% is far behind the expectation for immune checkpoint inhibitors (ICIs). Combination of ICIs with indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors is considered as an alternative solution and has proved effective in tremendous preclinical studies. However, the failure of phase III ECHO-301/KEYNOTE-252 trial seriously dampened the enthusiasm on the rationality of IDO1-targeting strategy. Fortunately, in spite of the ups and downs in the developmental journey of IDO1 inhibitors, multiple new approaches have been proposed to bridge the gap between lab to the clinic. Here, we review the recent advances in the development of small molecule inhibitors targeting IDO1 especially the new trend of IDO1 inhibitors after ECHO-301 clinical trials, including dual or pan-inhibitors targeting IDO1 and TDO or IDO2, apo-IDO1 inhibitors, IDO1 PROTACs, as well as other IDO1 inhibitors.
癌症免疫疗法已成为开发创新策略对抗癌症的新兴动力。尽管许多癌症患者从中获得了显著的临床获益，但~20%的总体平均反应率远低于免疫检查点抑制剂（ICI）的预期。ICI 与吲哚胺 2,3-双加氧酶-1（IDO1）抑制剂联合被认为是一种替代方案，并已在大量临床前研究中得到证实。然而，ECHO-301/KEYNOTE-252 三期临床试验的失败严重打击了人们对 IDO1 靶向策略合理性的热情。幸运的是，尽管 IDO1 抑制剂的研发历程跌宕起伏，但已经提出了多种新方法来弥合实验室与临床之间的差距。在这里，我们综述了针对 IDO1 的小分子抑制剂的最新进展，特别是 ECHO-301 临床试验后的 IDO1 抑制剂的新趋势，包括针对 IDO1 和 TDO 或 IDO2 的双靶点或泛靶点抑制剂、apo-IDO1 抑制剂、IDO1 PROTACs 以及其他 IDO1 抑制剂。
