Identification\nof a Compound Inhibiting Both the Enzymatic\nand Nonenzymatic Functions of Indoleamine 2,3-Dioxygenase 1

Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role\nin tumor\nimmune escape. Besides being a metabolic enzyme that catalyzes the\nfirst step of tryptophan catabolism, it also acts as a signal-transducing\nprotein, whose partnering with tyrosine phosphatase Src homology 2\n(SH2) domain-containing protein tyrosine phosphatase substrate (SHPs)\nand phosphatidylinositol-3-kinase (PI3K) regulatory subunit p85 promotes\nthe establishment of a sustained immunosuppressive phenotype. While\nIDO1 inhibitors typically interfere with its enzymatic activity, we\naimed to discover a more effective modulator capable of blocking not\nonly the enzymatic but also the signaling-mediated functions of IDO1.\nBy virtual screening, we identified the compound VS-15, which selectively\nbinds the heme-free form of IDO1, inhibits its enzymatic activity,\nand reduces the IDO1-mediated signaling pathway by negatively interfering\nwith its partnership with SHPs and PI3K regulatory subunit p85 as\nwell as with the IDO1 anchoring to the early endosomes in tumor cells.\nMoreover, VS-15 counteracts the TGF-βmediated immunosuppressive\nphenotype in dendritic cells and reduces the level of inhibition of\nT cell proliferation by suppressive monocytes isolated from patients\naffected by pancreatic cancer. Herein, we describe the discovery and\ncharacterization of a small molecule with an unprecedented mechanism\nof action, capable of inhibiting both the enzymatic and nonenzymatic\nactivities of IDO1 by binding to its apo-form. These results pave\nthe way for the development of next-generation IDO1 inhibitors with\na unique competitive advantage over the currently available modulators,\nthereby opening therapeutic opportunities in cancer immunotherapy.