The ups, downs and new trends of IDO1 inhibitors.

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.