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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2021

Open Access 01-12-2021 | Cancer Immunotherapy | Review

Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy

Authors: Kai Tang, Ya-Hong Wu, Yihui Song, Bin Yu

Published in: Journal of Hematology & Oncology | Issue 1/2021

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Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme enzyme that catalyzes the oxidation of L-tryptophan. Functionally, IDO1 has played a pivotal role in cancer immune escape via catalyzing the initial step of the kynurenine pathway, and overexpression of IDO1 is also associated with poor prognosis in various cancers. Currently, several small-molecule candidates and peptide vaccines are currently being assessed in clinical trials. Furthermore, the “proteolysis targeting chimera” (PROTAC) technology has also been successfully used in the development of IDO1 degraders, providing novel therapeutics for cancers. Herein, we review the biological functions of IDO1, structural biology and also extensively summarize medicinal chemistry strategies for the development of IDO1 inhibitors in clinical trials. The emerging PROTAC-based IDO1 degraders are also highlighted. This review may provide a comprehensive and updated overview on IDO1 inhibitors and their therapeutic potentials.
Literature
1.
Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10.PubMedCrossRef
2.
Coleman MF, Cozzo AJ, Pfeil AJ, Etigunta SK, Hursting SD. Cell intrinsic and systemic metabolism in tumor immunity and immunotherapy. Cancers. 2020;12:852.PubMedCentralCrossRef
3.
Emens LA, Ascierto PA, Darcy PK, Demaria S, Eggermont AMM, Redmond WL, et al. Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer. 2017;81:116–29.PubMedCrossRef
4.
Loo K, Tsai KK, Mahuron K, Liu J, Pauli ML, Sandoval PM, et al. Partially exhausted tumor-infiltrating lymphocytes predict response to combination immunotherapy. JCI Insight. 2017;2:e93433.PubMedCentralCrossRef
5.
Piechutta M, Berghoff AS. New emerging targets in cancer immunotherapy: the role of Cluster of Differentiation 40 (CD40/TNFR5). ESMO Open. 2019;4:e000510.PubMedPubMedCentralCrossRef
6.
7.
8.
Tokuyasu TA, Huang JD. A primer on recent developments in cancer immunotherapy, with a focus on neoantigen vaccines. J Cancer Metastasis Treat. 2018;4:2.CrossRef
9.
Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013;210:1389–402.PubMedPubMedCentralCrossRef
10.
Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer. 2014;18:3.CrossRef
11.
Crunkhorn S. Genentech dives deeper into the next wave of cancer immunotherapies. Nat Rev Drug Discov. 2014;13:879.PubMedCrossRef
12.
Stone TW, Stoy N, Darlington LG. An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci. 2013;34:136–43.PubMedCrossRef
13.
Fatokun A, Hunt N, Ball H. Indoleamine 2,3-dioxygenase 2 (IDO2) and thekynurenine pathway: characteristics and potential roles in health and disease. Amino Acids. 2013;45:1319–29.PubMedCrossRef
14.
Platten M, von Knebel DN, Oezen I, Wick W, Ochs K. Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors. Front Immunol. 2015;5:673.PubMedPubMedCentralCrossRef
15.
Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34:137–43.CrossRefPubMed
16.
Barth H, Raghuraman S. Persistent infectious diseases say—IDO. Role of indoleamine-2,3-dioxygenase in disease pathogenesis and implications for therapy. Crit Rev Microbiol. 2014;40:360–8.PubMedCrossRef
17.
Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 2012;72:5435–40.PubMedCrossRef
18.
Yeung AW, Terentis AC, King NJ, Thomas SR. Role of indoleamine 2,3-dioxygenase in health and disease. Clin Sci. 2015;129:601–72.CrossRef
19.
Kolawole AO, Hixon BP, Dameron LS, Chrisman IM, Smirnov VV. Catalytic activity of human indoleamine 2,3-dioxygenase (hIDO1) at low oxygen. Arch Biochem Biophys. 2015;15:47–57.CrossRef
20.
21.
Ball HJ, Sanchez-Perez A, Weiser S, Austin CJD, Astelbauer F, Miu J, et al. Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene. 2007;396:203–13.PubMedCrossRef
22.
Long GV, Dummer R, Hamid O, Gajewski T, Caglevic C, Dalle S, et al. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study. J Clin Oncol. 2018;36:3223–30.CrossRef
23.
Luke JJ, Tabernero J, Joshua A, Desai J, Varga AI, Moreno V, et al. BMS-986205, an indoleamine 2, 3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (nivo): updated safety across all tumor cohorts and efficacy in advanced bladder cancer (advBC). J Clin Oncol. 2019;37:358.CrossRef
24.
Nayak A, Hao Z, Sadek R, Vahanian N, Ramsey WJ, Kennedy E, et al. A Phase I study of NLG919 for adult patients with recurrent advanced solid tumors. J Immunother Cancer. 2014;2:250.CrossRef
25.
Qian F, Villella J, Wallace PK, Mhawech-Fauceglia P, Tario JD Jr, Andrews C, et al. Efficacy of levo-1-methyl tryptophan and dextro-1-methyl tryptophan in reversing indoleamine-2,3-dioxygenase–mediated arrest of T-cell proliferation in human epithelial ovarian cancer. Cancer Res. 2009;69:5498–504.PubMedCrossRef
26.
Tumang J, Gomes B, Wythes M, Crosignani S, Bingham P, Bottemanne P, et al. PF-06840003: a highly selective IDO-1 inhibitor that shows good in vivo efficacy in combination with immune checkpoint inhibitors. Cancer Res. 2016;76:abstract nr 4863.CrossRef
27.
Hu MX, Zhou WL, Wang YJ, Yao DP, Ye TH, Yao YQ, et al. Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1. Acta Pharm Sin B. 2020;10:1943–53.PubMedPubMedCentralCrossRef
28.
Ye ZX, Yue LX, Shi JC, Shao MM, Wu T. Role of IDO and TDO in cancers and related diseases and the therapeutic implications. J Cancer. 2019;10:2771–82.PubMedPubMedCentralCrossRef
29.
Dey M, Chang AL, Miska J, Lesniak MS. The role of regulatory T cells and indoleamine-2,3-dioxygenase in brain tumor immunosuppression. In: Translational immunotherapy of brain tumors. Elsevier Inc. 2017;33–61.
30.
Tomek P, Palmer BD, Flanagan JU, Sun C, Raven EL, Ching LM. Discovery and evaluation of inhibitors to the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1): probing the active site-inhibitor interactions. Eur J Med Chem. 2017;126:983–96.PubMedCrossRef
31.
Hornyák L, Dobos N, Koncz G, Karányi Z, Páll D, Szabó Z, et al. The role of indoleamine-2,3-dioxygenase in cancer development, diagnostics, and therapy. Front Immunol. 2018;9:151.PubMedPubMedCentralCrossRef
32.
Zhai L, Ladomersky E, Lenzen A, Nguyen B, Patel R, Lauing KL, et al. IDO1 in cancer: a Gemini of immune checkpoints. Cell Mol Immunol. 2018;15:447–57.PubMedPubMedCentralCrossRef
33.
Chen B, Alvarado DM, Iticovici M, Kau NS, Park H, Parikh PJ, et al. Interferon-induced IDO1 mediates radiation resistance and is a therapeutic target in colorectal cancer. Cancer Immunol Res. 2020;8:451–64.PubMedPubMedCentralCrossRef
34.
Vacchelli E, Aranda F, Eggermont A, Fridman CS, Tartour E, Eugene P, et al. Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology. 2014;3:e957994.PubMedPubMedCentralCrossRef
35.
Kozuma Y, Takada K, Toyokawa G, Kohashi K, Shimokawa M, Hirai F, et al. Indoleamine 2,3-dioxygenase 1 and programmed cell death-ligand 1 co-expression correlates with aggressive features in lung adenocarcinoma. Eur J Cancer. 2018;101:20–9.PubMedCrossRef
36.
Bezu L, Keep O, Cerrato G, Pol J, Fucikova J, Spisek R, et al. Trial watch: peptide-based anticancer vaccines. Oncoimmunology. 2015;4:e974411.CrossRef
37.
Werfel TA, Elion DL, Rahman B, Hicks DJ, Sanchez V, Gonzales-Ericsson PI, et al. Treatment-induced tumor cell apoptosis and secondary necrosis drive tumor progression in the residual tumor microenvironment through MerTK and IDO1. Cancer Res. 2019;79:171–82.PubMedCrossRef
38.
39.
Carbotti G, Barisione G, Airoldi I, Mezzanzanica D, Bagnoli M, Ferrero S, et al. IL-27 induces the expression of IDO and PD-L1 in human cancer cells. Oncotarget. 2015;6:43267–80.PubMedPubMedCentralCrossRef
40.
Zhai LJ, Ladomersky E, Lauing KL, Wu MJ, Genet M, Gritsina G, et al. Infiltrating T cells increase IDO1 expression in glioblastoma and contribute to decreased patient aurvival. Clin Cancer Res. 2017;23:6650–60.PubMedPubMedCentralCrossRef
41.
Liu YY, Liang XY, Yin XN, Lv JD, Tang K, Ma JW, et al. Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells. Nat Commun. 2017;8:15207.PubMedPubMedCentralCrossRef
42.
Blache CA, Manuel ER, Kaltcheva TI, Wong AN, Joshua DI, Ellenhorn AN, et al. Systemic delivery of Salmonella typhimurium transformed with IDO shRNA enhances intratumoral vector colonization and suppresses tumor growth. Cancer Res. 2012;72:6447–56.PubMedPubMedCentralCrossRef
43.
Wei LJ, Zhu SS, Li MH, Li FX, Wei F, Liu JT, et al. High indoleamine 2,3-dioxygenase is correlated with microvessel density and worse prognosis in breast cancer. Front Immunol. 2018;9:724.PubMedPubMedCentralCrossRef
44.
Zhai L, Spranger S, Binder DC, Gritsina G, Lauing KL, Giles FJ, et al. Molecular pathways: targeting IDO1 and other tryptophan dioxygenases for cancer immunotherapy. Clin Cancer Res. 2015;21:5427–33.PubMedPubMedCentralCrossRef
45.
Bishnupuri KS, Alvarado DM, Khouri AN, Shabsovich M, Chen BS, Dieckgraefe BK. IDO1 and Kynurenine pathway metabolites activate PI3K-Akt signaling in the neoplastic colon epithelium to promote cancer cell proliferation and inhibit apoptosis. Cancer Res. 2019;79:1138–50.PubMedPubMedCentralCrossRef
46.
47.
Wang LT, Chiou SS, Chai CY, His E, Yokoyama KK, Wang SN, et al. Intestine-specific homeobox gene ISX integrates IL6 signaling, tryptophan catabolism, and immune suppression. Cancer Res. 2017;77:4065–77.PubMedCrossRef
48.
49.
Crosignani S, Bingham P, Bottemanne P, Cannelle H, Cauwenberghs S, Cordonnier M, et al. Discovery of a novel and selective indoleamine 2,3-dioxygenase (IDO-1) inhibitor 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and its characterization as a potential clinical candidate. J Med Chem. 2017;60:9617–29.PubMedCrossRef
50.
Liu YY, Liang XY, Dong WQ, Fang Y, Lv JD, Zhang TZ, et al. Tumor-repopulating cells induce PD-1 expression in CD8+ T cells by transferring kynurenine and AhR activation. Cancer Cell. 2018;33:480–94.PubMedCrossRef
51.
Cheong JE, Sun L. Targeting the IDO1/TDO2-KYN-AhR pathway for cancer immunotherapy-challenges and opportunities. Trends Pharmacol Sci. 2018;39:307–25.PubMedCrossRef
52.
Röhrig UF, Awad L, Grosdidier A, Larrieu P, Stroobant V, Colau D, et al. Rational design of indoleamine 2,3-dioxygenase inhibitors. J Med Chem. 2010;53:1172–89.PubMedCrossRef
53.
Lewis-Ballester A, Pham KN, Batabyal D, Karkashon S, Bonanno JB, Poulos TL, et al. Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1. Nat Commun. 2017;8:1693.PubMedPubMedCentralCrossRef
54.
Sugimoto H, Oda S, Otsuki T, Hino T, Yoshida T, Shiro Y. Crystal structure of human indoleamine 2,3 dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. Proc Natl Acad Sci USA. 2006;103:2611–6.PubMedCrossRefPubMedCentral
55.
Littlejohn TK, Takikawa O, Truscott RJ, Walker MJ. Asp274 and his346 are essential for heme binding and catalytic function of human indoleamine 2,3-dioxygenase. J Biol Chem. 2003;278:29525–31.PubMedCrossRef
56.
Rohrig UF, Reynaud A, Majjigapu SR, Vogel P, Pojer F, Zoete V. Inhibition mechanisms of indoleamine 2,3-dioxygenase 1 (IDO1). J Med Chem. 2019;62:8784–95.PubMedCrossRef
57.
Rohrig UF, Majjigapu SR, Vogel P, Zoete V, Michielin O. Challenges in the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) Inhibitors. J Med Chem. 2015;58:9421–37.PubMedCrossRef
58.
Zhang Y, Kang SA, Mukherjee T, Bale S, Crane BR, Begley TP, et al. Crystal structure and mechanism of tryptophan 2,3-dioxygenase, a heme enzyme involved in tryptophan catabolism and in quinolinate biosynthesis. Biochemistry. 2007;46:145–55.PubMedCrossRef
59.
Luo SK, Xu K, Xiang SY, Chen J, Chen CY, Guo CX, et al. High-resolution structures of inhibitor complexes of human indoleamine 2,3-dioxygenase 1 in a new crystal form. Acta Crystallogr F Struct Biol Commun. 2018;74:717–24.PubMedPubMedCentralCrossRef
60.
Serafini M, Torre E, Aprile S, Grosso ED, Gesu A, Griglio A, et al. Discovery of highly potent benzimidazole derivatives as indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors: from structure-based virtual screening to in vivo pharmacodynamic activity. J Med Chem. 2020;63:3047–65.PubMedCrossRef
61.
Griglio A, Torre E, Serafini M, Bianchi A, Schmid R, Coda ZG. A multicomponent approach in the discovery of indoleamine 2,3-dioxygenase 1 inhibitors: synthesis, biological investigation and docking studies. Bioorg Med Chem Lett. 2018;28:651–7.PubMedCrossRef
62.
63.
Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019;20:1083–97.
64.
Sonpavde G, Necchi A, Gupta S, Steinberg GD, Gschwend JE, Van Der Heijden MS, et al. ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer. Future Oncol. 2020;16:4359–68.
65.
Nayak-Kapoor A, Hao ZL, Sadek R, Dobbins R, Marshall L, Vahanian NN, et al. Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. J Immunother Cancer. 2018;6:61.PubMedPubMedCentralCrossRef
66.
Jung KH, LoRusso P, Burris H, Gordon M, Bang YJ, Hellmann MD, et al. Phase I study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor Navoximod (GDC-0919) administered with PD-L1 inhibitor (Atezolizumab) in advanced solid tumors. Clin Cancer Res. 2019;25:3220–8.PubMedPubMedCentralCrossRef
67.
Reardon DA, Desjardins A, Rixe O, Cloughesy T, Alekar S, Williams JH, et al. A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma. Invest New Drugs. 2020;6:1784–95.CrossRef
68.
Gomes B, Driessens G, Bartlett D, Cloughesy T, Alekar S, Williams JH, et al. Characterization of the selective indoleamine 2,3-dioxygenase-1 (IDO1) catalytic inhibitor EOS200271/PF-06840003 supports IDO1 as a critical resistance mechanism to PD-(L)1 blockade therapy. Mol Cancer Ther. 2018;17:2530–42.PubMedCrossRef
69.
Fox E, Oliver T, Rowe M, Thomas S, Zakharia Y, Gilman PB, et al. Indoximod: an immunometabolic adjuvant that empowers T cell activity in cancer. Front Oncol. 2018;8:370.PubMedPubMedCentralCrossRef
70.
Metz R, Rust S, Duhadaway JB, Mautino MR, Munn DH, Vahanian NN, et al. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan. Oncoimmunology. 2012;1:1460–8.PubMedPubMedCentralCrossRef
71.
Brincks EL, Adams J, Wang LF, Turner B, Marcinowicz A, Ke JY, et al. Indoximod opposes the immunosuppressive effects mediated by IDO and TDO via modulation of AhR function and activation of mTORC1. Oncotarget. 2020;11:2438–61.PubMedPubMedCentralCrossRef
72.
Kumar S, Jaipuri FA, Waldo JP, Potturi H, Marcinowicz A, Adams J, et al. Discovery of indoximod prodrugs and characterization of clinical candidate NLG802. Eur J Med Chem. 2020;198:112373.PubMedCrossRef
73.
Soliman H, Khambati F, Han HS, Ismail-Khan R, Bui MM, Sullivan DM, et al. A phase-1/2 study of adenovirus-p53 transduced dendritic cell vaccine in combination with Indoximod in metastatic solid tumors and invasive breast cancer. Oncotarget. 2018;9:10110–7.PubMedPubMedCentralCrossRef
74.
Dhiman V, Giri KK, Suresh PS, Zainuddin M, Rajagopal S, Mullangi R. Determination of epacadostat, a novel IDO1 inhibitor in mouse plasma by LC-MS/MS and its application to a pharmacokinetic study in mice. Biomed Chromatogr. 2017;31:e3794.CrossRef
75.
Jochems C, Fantini M, Fernando RI, Kwilas AR, Donahue RN, Lepone LM, et al. The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells. Oncotarget. 2016;7:37762–72.PubMedPubMedCentralCrossRef
76.
Gibney GT, Hamid O, Lutzky J, Olszanski AJ, Mitchell TC, Gajewski TF, et al. Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma. J Immunother Cancer. 2019;7:80.PubMedPubMedCentralCrossRef
77.
Epacadostat shows value in two SCCHN trials. Cancer Discov. 2017;7:OF2.
78.
Blocking IDO1 helps shrink bladder, cervical tumors. Cancer Discov. 2018;8:OF3.
79.
Cheong JE, Ekkati A, Sun LJ. A patent review of IDO1 inhibitors for cancer. Expert Opin Ther Pat. 2018;28:317–30.PubMedCrossRef
80.
81.
Iversen TZ, Engell-Noerregaard L, Ellebaek E, Andersen R, Larsen SK, Bjoern J, et al. Long-lasting disease stabilization in the absence of toxicity in metastatic lung cancer patients vaccinated with an epitope derived from indoleamine 2,3 dioxygenase. Clin Cancer Res. 2014;20:221–32.PubMedCrossRef
82.
Bjoern J, Iversen TZ, Nitschke NJ, Andersen MH, Svane IM. Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2,3-dioxygenase in combination with ipilimumab. Cytotherapy. 2016;18:1043–55.PubMedCrossRef
83.
Souza LC, Jesse CR, Del FL, Gomes MG, Goes ATR, Filho CB, et al. Swimming exercise prevents behavioural disturbances induced by an intracerebroventricular injection of amyloid-β(1–42) peptide through modulation of cytokine/NF-kappaB pathway and indoleamine-2,3-dioxygenase in mouse brain. Behav Brain Res. 2017;331:1–13.PubMedCrossRef
84.
Yue EW, Douty B, Wayland B, Bower M, Liu XD, Leffet L, et al. Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model. J Med Chem. 2009;52:7364–7.PubMedCrossRef
85.
Yue EW, Sparks R, Polam P, Modi D, Douty B, Wayland B, et al. INCB24360 (epacadostat), a highly potent and selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor for immuno-oncology. ACS Med Chem Lett. 2017;8:486–91.PubMedPubMedCentralCrossRef
86.
Van den Eynde BJ, van Baren N, Baurain JF. Is there a clinical future for Ido1 inhibitors after the failure of epacadostat in melanoma? Annu Rev Cancer Biol. 2020;4(241–256):89.
87.
88.
Nelp MT, Kates PA, Hunt JT, Newitt JA, Balog A, Maley D, et al. Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form. Proc Natl Acad Sci U S A. 2018;115:3249–54.PubMedPubMedCentralCrossRef
89.
Mario RM, Firoz AJ, Jesse W, Kumar S, Adams J, Allen CV, et al. NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy. Cancer Res. 2013;73:491.CrossRef
90.
Kumar S, Waldo JP, Jaipuri FA, Marcinowicz A, Van Allen C, Adams J, et al. Discovery of clinical candidate (1R,4r)-4-((R)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyc lohexan-1-ol (navoximod), a potent and selective inhibitor of indoleamine 2,3-dioxygenase 1. J Med Chem. 2019;62:6705–33.PubMedCrossRef
91.
Muller AJ, Malachowski GC, Prendergast GC. Indoleamine 2,3-dioxygenase in cancer: targeting pathological immune tolerance with small-molecule inhibitors. Expert Opin Ther Targets. 2005;9:831–49.PubMedCrossRef
92.
Fu TH, He QM, Sharma P. The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res. 2011;71:5445–54.PubMedCrossRef
93.
Frank CD, Karim AB, Lillian LS. Identification and characterization of the IDO1 inhibitor LY3381916. Cancer Res. 2018;78:5245.CrossRef
94.
Hu B, Zhou Y, Sun D, Yang Y, Liu Y, Li X, et al. PROTACs: new method to degrade transcription regulating proteins. Eur J Med Chem. 2020;207:112698.PubMedCrossRef
95.
Martín-Acosta P, Xiao X. PROTACs to address the challenges facing small molecule inhibitors. Eur J Med Chem. 2021;210:112993.PubMedCrossRef
96.
Toure M, Crews CM. Small-molecule PROTACS: new approaches to protein degradation. Angew Chem Int Ed Engl. 2016;55:1966–73.PubMedCrossRef
97.
Zeng S, Huang W, Zheng X, Ch LY, Zhang Z, Wang J, et al. Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: recent progress and future challenges. Eur J Med Chem. 2021;210:112981.PubMedCrossRef
Metadata
Title
Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy
Authors
Kai Tang
Ya-Hong Wu
Yihui Song
Bin Yu
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2021
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-021-01080-8

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