Exploring LY3381916: A Potent IDO1 Inhibitor for Cancer Immunotherapy

Indoleamine 2,3-dioxygenase 1 (IDO1), a heme-dependent enzyme, plays a crucial role in tryptophan catabolism, leading to the production of immunosuppressive compounds. The combination of IDO1 inhibitors with PD-1/PD-L1-targeted therapies has shown promise in early clinical trials, indicating that IDO1 expression may limit the effectiveness of checkpoint therapies for some patients.

Cancer cells can express IDO1 either in response to immune signals or intrinsically. In the search for potent and selective IDO1 inhibitors, LY3381916 was identified. It shows high selectivity for inhibiting cell-based IDO1 activity and binds to apo-IDO1, the form lacking heme. X-ray crystallography confirmed that LY3381916 occupies the heme-binding pocket of apo-IDO1. The drug's mechanism requires the turnover of mature heme-bound IDO1 for substantial inhibition, and pre-clinical pharmacokinetic/pharmacodynamic modeling suggests once-daily dosing can maintain over 90% inhibition.

LY3381916 does not act as an aryl hydrocarbon receptor (AHR) agonist, unlike some heme-binding IDO1 inhibitors, which could limit their effectiveness in relieving IDO1-dependent immunosuppression. In pre-clinical tumor models, LY3381916 was found to enhance the activity of an anti-PD-L1 antibody, associated with an increased T cell response. The drug also exhibits significant central nervous system penetration.

LY3381916 is currently under investigation in a Phase I clinical trial, and the data gathered so far suggest that its further development may be warranted for the treatment of cancer.