Indole-pyridinyl-ethanones as Novel Inhibitors of Indoleamine 2,3-Dioxygenase (IDO), a Promising Target forAnti-Cancer Immunotherapy

Immunotherapy is a promising novel and validated strategy for cancer therapy. It consists of the therapeutic vaccination of patients to stimulate their (natural) immune system against cancer cells. However, this approach showed a limited efficacy in vivo because cancer cells develop enzymatic mechanisms allowing tumors to resist or escape immune rejection. Among the enzymes involved, indoleamine 2,3-dioxygenase (IDO) was identified as a potential actor. IDO catalyses the rapid degradation of tryptophan (Trp) into N-formylkynurenine. This results in a local Trp depletion that severely affects T-cells proliferation and is thereby deeply immunosuppressive. Recently, the team of Prof. Van den Eynde demonstrated that many human tumors express IDO in a constitutive manner and that this expression allows cancer cells to escape immune rejection. IDO was thus clearly identified as an attractive target for the development of inhibitors. [1] The recent elucidation of the three-dimensional structures of IDO[2], in complex with phenylimidazole and the cyanide ion (CN¯), provide important results for the structure-based drug discovery and design of novel IDO inhibitors. In the present work, we applied virtual screening for the discovery of new IDO inhibitors. As a result, five novel scaffolds with inhibitory potencies in the micromolar range were identified. Among these, the most promising candidate (1: IC50 = 65 µM) was selected and its inhibitory potency improved by chemical modifications. This led to a 7-fold improvement of the inhibitory potency of the hit selected. In this communication, the identification of 1, the synthesis and biological evaluation of analogues as well as a modeling study explaining the SAR will be presented. [3]