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Review
. 2017 Dec 15;77(24):6795-6811.
doi: 10.1158/0008-5472.CAN-17-2285.

Discovery of IDO1 Inhibitors: From Bench to Bedside

George C Prendergast  1 , William P Malachowski  2 , James B DuHadaway  3 , Alexander J Muller  3
Affiliations
Review

Discovery of IDO1 Inhibitors: From Bench to Bedside

George C Prendergast et al. Cancer Res. .

Abstract

Small-molecule inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) are emerging at the vanguard of experimental agents in oncology. Here, pioneers of this new drug class provide a bench-to-bedside review on preclinical validation of IDO1 as a cancer therapeutic target and on the discovery and development of a set of mechanistically distinct compounds, indoximod, epacadostat, and navoximod, that were first to be evaluated as IDO inhibitors in clinical trials. As immunometabolic adjuvants to widen therapeutic windows, IDO inhibitors may leverage not only immuno-oncology modalities but also chemotherapy and radiotherapy as standards of care in the oncology clinic. Cancer Res; 77(24); 6795-811. ©2017 AACR.

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Conflict of interest statement

Conflict of Interest Statement

The authors state a conflict of interest as shareholders, W.J.M. and G.C.P. as compensated scientific advisors, and G.C.P. as a former grant recipient of NewLink Genetics Corporation, based on their roles as inventors of IDO intellectual property licensed to NewLink as described in U.S. Patents Nos. 7705022, 7714139, 8008281, 8058416, 8383613, 8389568, 8436151, 8476454 and 8586636.

Figures

Figure 1
Figure 1. Impact of IDO1 immunometablism in cancer
IDO1 expression patterns in human cancer are complex, occurring heterogeneously in malignant, immune, stromal and vascular cells within the tumor microenvironment and in antigen-presenting cells (APC) within tumor-draining lymph nodes. TDO and IDO2 are more narrowly expressed than IDO1 in human cancers, with TDO mainly in malignant cells and IDO2 mainly in immune cells. TDO is highly expressed in tumors independently or in parallel with IDO1; it has been ascribed both similar and distinct functions contributing to metastatic progression. IDO2 is expressed in antigen-presenting cells including B cells where it may influence IDO1 function (88); IDO2 is infrequently overexpressed in tumor cells. Tryptophan catabolism in tumor cells leads to local kynurenine generation and tryptophan depletion in the tumor microenvironment, enabling local suppression of T effector cells (Teff), functional licensing of myeloid-derived suppressor cells and recruitment of the tumor vasculature ❶. As conditioned by tumor cells, the tumor microenvironment recruits stromal cells expressing IDO1 and innate immune cells expressing IDO1 and IDO2, including cancer-associated fibroblasts, myeloid-derived suppressor cells and tumor-associated macrophages, the latter of which generate IL-6 and CCL2 in a manner dependent on local IDO1 activity, positively reinforcing the function of these cells and regulatory T cells that arrive ❷. Tumor antigens absorbed and presented to T cells by antigen-presenting cells which have roved away to a local draining lymph node ❸ promote the formation of activated T cells or tolerizing T cells (i.e. regulatory T cells), depending on whether the APC expresses IDO1 and perhaps IDO2 ❹. Antigen-specific T cells leave the lymph node and enter the vasculature ❺ where they can engage the primary tumor and contribute to the immune attitude of a latent metastatic niche ❻. APC, antigen-presenting cell; CAF, cancer-associated fibroblast; CCL2, a potent myeloid cell attractant and pro-differentiation agent, including for MDSC and TAM; IL-6, the master pro-inflammatory cytokine interleukin-6, which in tumors helps sustain myeloid-based and lymphoid-based immunosuppression and promotes neovascularization; MDSC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage; Teff, activated effector T cell; Treg, regulatory T cell.
Figure 2
Figure 2. Sites of IDO1 expression and effector function in tumors
IDO1 is expressed in tumor cells, inflammatory/antigen-presenting cells and stromal cells under the diverse controls indicated in different tumor types ❶. In tumor cells, Bin1 attenuation and PGE2 production are key modifiers of IDO1 expression, which is transcriptionally controlled in different tumor settings by the interferon/Jak/STAT, ONC and PAMP signaling pathways. In inflammatory/antigen-presenting cells, B7 ligand reverse signaling is a major driver of IDO1 expression, most notably by CTLA-4 binding to CD80/CD86 or PD-1 binding to PD-L1 on the cell surface. Thus, tolerance mediated by PD-1 and CTLA-4 from regulatory T cells is intertwined with IDO1 upregulation, engendering a feed-forward loop to suppress adaptive immunity. In stromal cells, IDO1 can also be upregulated variably by interferon and PAMP signaling and PGE2 production. Altogether, IDO1 upregulation in tumor cells and the tumor microenvironment leads to locoregional deprivation of tryptophan and production of its catabolite kynurenine ❷. Responding cells interpret Trp insufficiency through the mTORC1 and GCN2/eIF-2 pathways, whereas kynurenine acts as a native ligand for the xenobiotic receptor AHR ❸. Downstream effector pathways with responsive target regulators are shown along with the different types of responding cells. AHR, arylhydrocarbon receptor; APC, antigen-presenting cell; B7, T cell co-receptor-ligand complexes (e.g. CTLA4-CD80/86 or PD1-PDL1) which stimulate signals into T cells and ‘reverse signals’ into antigen-presenting cells; IFN, interferon; DAMP, damage-associated molecular pattern (e.g. extracellular HMGB1 or ATP ligands for TLR4 or A2A receptors, respectively); eIF-2, a key regulatory factor for mRNA translation initiation; GCN2, a stress response kinase that is activated by binding uncharged tRNA, indicative of amino acid starvation; ONC, oncogenic ligand-receptor signaling complex (e.g. EGFR); mTORC1, a master metabolic regulatory complex that monitors amino acid pools for cell growth or autophagic decisions; PAMP, pathogen-associated molecular pattern (e.g. LPS or CpG ligands of Toll-like receptors [TLR]); Teff, activated effector T cells; Treg, regulatory T cells.
Figure 3
Figure 3. IDO1 inhibitors and their impact on tryptophan immunocatabolism
Tryptophan (Trp) catabolism proceeds through one of two pathways in mammals, leading to production of nicotinamide adenine dinucleotide or serotonin. The kynurenine pathway accounts for ~95% and the serotonin pathway for 5% of tryptophan catabolism ❶, with possible implications on affect and quality of life in cancer patients where the kynurenine pathway is driven by IDO/TDO dysregulation. Epacadostat is >100-fold selective for IDO1 against TDO and represents a highly specific agent with competitive inhibitory kinetics for tryptophan binding. Navoximod is ~20-fold selective for IDO1 against TDO and exhibits non-competitive inhibitory kinetics for tryptophan binding. BMS-986205 is an irreversible inhibitor of IDO1 that is highly specific for that enzyme. None of these agents inhibit IDO2 appreciably. Indoximod is not a direct enzyme inhibitor and its action is complex; it has been reported to indirectly inhibit IDO2 and/or IDO1 in some settings. Its primary mechanism of action appear to be downstream, in its high potency as a tryptophan mimetic interpreted by mTORC1 as L-tryptophan under conditions of high tryptophan catabolism and autophagy due to tryptophan deprivation by any catabolic enzyme. The targeted enzyme inhibitors affect both catabolic effector signaling pathways ❷. Kynurenine functions as a native ligand for the pro-inflammatory receptor AHR, which activates downstream gene expression ❸. Tryptophan deprivation triggers starvation-induced signals mediated by upregulation of the general stress kinase GCN2 and downregulation of the mTORC1 complex (which monitors amino acid pools for growth versus autophagy decisions, which are critical for T cell function) ❹.
Figure 4
Figure 4. Discovery teams in preclinical proof of concept
(A.) NewLink Genetics team with academic collaborators. Left to right, Alexander Muller (Lankenau), Nicholas Vahanian (New Link), Andrew Mellor (Georgia), David Munn (Georgia), Charles Link (New Link), Mario Mautino (New Link), George Prendergast (Lankenau). The New Link IDO1 program was initiated by Mario Mautino after the company in-licensed founding intellectual property from the Munn/Mellor team at the Medical College of Georgia (now Augusta University) and the Prendergast/Muller team at the Lankenau Institute for Medical Research (LIMR). (B.) Lankenau team. Left to right, George Prendergast, Alexander Muller, James DuHadaway, William Malachowski (Bryn Mawr College). (C.) Incyte and Lankenau. Left to right, Peggy Scherle, a key proponent of the IDO1 program at Incyte, with spouse Alexander Muller, who initiated the IDO1 program at Lankenau with George Prendergast. (D.) Incyte medicinal chemistry team contributing to the development of epacadostat (99). Left to right, Andrew Combs, Dilip Modi, Joe Glenn, Brent Douty, Padmaja Polam, Brian Wayland, Rick Sparks, Wenyu Zhu, and Eddy Yue.
Figure 5
Figure 5. Discovery timelines in preclinical proof of concept
Key milestones are cited in the discovery and preclinical validation of IDO1 as a cancer therapeutic target as referenced in the Figure. IP, intellectual property; MDSC, myeloid-derived suppressor cells; POC, proof of concept; SAR, structure-activity relationship analysis (for inhibitor class noted).
Figure 6
Figure 6. IDO1 inhibitor structures and intermediates
(A.) Indoximod. A 1-methyl derivative of D-tryptophan interpreted by mTORC1 in cells as L-tryptophan. (B.) 4-PI. Founding compound of the phenylimidazole chemotype series. (C.) N3-benzyl derivative elaborating this site. (D.) Ortho-hydroxyl modifications which elaborate potency. (E.) Navoximod (NLG-919), clinical lead from the imidazoisoindole series. (F.) Epacadstat discovery milestones. 1, original hit including critical hydroxyamidine (blue). 2, preclinical proof of concept lead compound (INCB14943). 3, epacadostat (INCB024360) as final clinical lead.
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