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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.

Crosignani S, Bingham P, Bottemanne P, Cannelle H, Cauwenberghs S, Cordonnier M, Dalvie D, Deroose F, Feng JL, Gomes B, Greasley S, Kaiser SE, Kraus M, Négrerie M, Maegley K, Miller N, Murray BW, Schneider M, Soloweij J, Stewart AE, Tumang J, Torti VR, Van Den Eynde B, Wythes M
J Med Chem 60 9617-9629 (2017)
Cited: 39 times
EuropePMC logo PMID: 29111717

Abstract

Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. The structure-activity relationship around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode. Clinical candidate 6 shows good potency in an IDO-1 human whole blood assay and also shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties, including a predicted half-life of 16-19 h.

Reviews - 5whr mentioned but not cited (1)

  1. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy. Tang K, Wu YH, Song Y, Yu B. J Hematol Oncol 14 68 (2021)

Articles - 5whr mentioned but not cited (3)

  1. Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO-1) Inhibitors Based on Ortho-Naphthaquinone-Containing Natural Product. Zhao H, Sun P, Guo W, Wang Y, Zhang A, Meng L, Ding C. Molecules 24 E1059 (2019)
  2. Inhibition Mechanism of Indoleamine 2, 3-Dioxygenase 1 (IDO1) by Amidoxime Derivatives and Its Revelation in Drug Design: Comparative Molecular Dynamics Simulations. Liu X, Zhang Y, Duan H, Luo Q, Liu W, Liang L, Wan H, Chang S, Hu J, Shi H. Front Mol Biosci 6 164 (2019)
  3. Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. Röhrig UF, Majjigapu SR, Vogel P, Reynaud A, Pojer F, Dilek N, Reichenbach P, Ascenção K, Irving M, Coukos G, Michielin O, Zoete V. J Enzyme Inhib Med Chem 37 1773-1811 (2022)


Reviews citing this publication (10)

  1. Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan-Kynurenine-Aryl Hydrocarbon Axis. Labadie BW, Bao R, Luke JJ. Clin Cancer Res 25 1462-1471 (2019)
  2. Kynurenines as a Novel Target for the Treatment of Malignancies. Mor A, Tankiewicz-Kwedlo A, Pawlak D. Pharmaceuticals (Basel) 14 606 (2021)
  3. The therapeutic potential of targeting tryptophan catabolism in cancer. Opitz CA, Somarribas Patterson LF, Mohapatra SR, Dewi DL, Sadik A, Platten M, Trump S. Br J Cancer 122 30-44 (2020)
  4. A patent review of IDO1 inhibitors for cancer. Cheong JE, Ekkati A, Sun L. Expert Opin Ther Pat 28 317-330 (2018)
  5. The immunosuppressive role of indoleamine 2, 3-dioxygenase in glioblastoma: mechanism of action and immunotherapeutic strategies. Hosseinalizadeh H, Mahmoodpour M, Samadani AA, Roudkenar MH. Med Oncol 39 130 (2022)
  6. The Role of Metabolism in Tumor Immune Evasion: Novel Approaches to Improve Immunotherapy. Cruz-Bermúdez A, Laza-Briviesca R, Casarrubios M, Sierra-Rodero B, Provencio M. Biomedicines 9 361 (2021)
  7. Promising Nanomedicines of Shikonin for Cancer Therapy. Yan C, Li Q, Sun Q, Yang L, Liu X, Zhao Y, Shi M, Li X, Luo K. Int J Nanomedicine 18 1195-1218 (2023)
  8. Recent advances in the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. Wang XX, Sun SY, Dong QQ, Wu XX, Tang W, Xing YQ. Medchemcomm 10 1740-1754 (2019)
  9. Targeting Indoleamine Dioxygenase and Tryptophan Dioxygenase in Cancer Immunotherapy: Clinical Progress and Challenges. Peng X, Zhao Z, Liu L, Bai L, Tong R, Yang H, Zhong L. Drug Des Devel Ther 16 2639-2657 (2022)
  10. The kynurenine pathway presents multi-faceted metabolic vulnerabilities in cancer. León-Letelier RA, Dou R, Vykoukal J, Sater AHA, Ostrin E, Hanash S, Fahrmann JF. Front Oncol 13 1256769 (2023)

Articles citing this publication (25)

  1. A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma. Reardon DA, Desjardins A, Rixe O, Cloughesy T, Alekar S, Williams JH, Li R, Taylor CT, Lassman AB. Invest New Drugs 38 1784-1795 (2020)
  2. Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form. Nelp MT, Kates PA, Hunt JT, Newitt JA, Balog A, Maley D, Zhu X, Abell L, Allentoff A, Borzilleri R, Lewis HA, Lin Z, Seitz SP, Yan C, Groves JT. Proc. Natl. Acad. Sci. U.S.A. 115 3249-3254 (2018)
  3. The trans-omics landscape of COVID-19. Wu P, Chen D, Ding W, Wu P, Hou H, Bai Y, Zhou Y, Li K, Xiang S, Liu P, Ju J, Guo E, Liu J, Yang B, Fan J, He L, Sun Z, Feng L, Wang J, Wu T, Wang H, Cheng J, Xing H, Meng Y, Li Y, Zhang Y, Luo H, Xie G, Lan X, Tao Y, Li J, Yuan H, Huang K, Sun W, Qian X, Li Z, Huang M, Ding P, Wang H, Qiu J, Wang F, Wang S, Zhu J, Ding X, Chai C, Liang L, Wang X, Luo L, Sun Y, Yang Y, Zhuang Z, Li T, Tian L, Zhang S, Zhu L, Chang A, Chen L, Wu Y, Ma X, Chen F, Ren Y, Xu X, Liu S, Wang J, Yang H, Wang L, Sun C, Ma D, Jin X, Chen G. Nat Commun 12 4543 (2021)
  4. A highly efficient modality to block the degradation of tryptophan for cancer immunotherapy: locked nucleic acid-modified antisense oligonucleotides to inhibit human indoleamine 2,3-dioxygenase 1/tryptophan 2,3-dioxygenase expression. Klar R, Michel S, Schell M, Hinterwimmer L, Zippelius A, Jaschinski F. Cancer Immunol Immunother 69 57-67 (2020)
  5. Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors. Li D, Deng Y, Achab A, Bharathan I, Hopkins BA, Yu W, Zhang H, Sanyal S, Pu Q, Zhou H, Liu K, Lim J, Fradera X, Lesburg CA, Lammens A, Martinot TA, Cohen RD, Doty AC, Ferguson H, Nickbarg EB, Cheng M, Spacciapoli P, Geda P, Song X, Smotrov N, Abeywickrema P, Andrews C, Chamberlin C, Mabrouk O, Curran P, Richards M, Saradjian P, Miller JR, Knemeyer I, Otte KM, Vincent S, Sciammetta N, Pasternak A, Bennett DJ, Han Y. ACS Med Chem Lett 12 389-396 (2021)
  6. Discovery of Imidazoisoindole Derivatives as Highly Potent and Orally Active Indoleamine-2,3-dioxygenase Inhibitors. Tu W, Yang F, Xu G, Chi J, Liu Z, Peng W, Hu B, Zhang L, Wan H, Yu N, Jin F, Hu Q, Zhang L, He F, Tao W. ACS Med Chem Lett 10 949-953 (2019)
  7. Mapping the Binding Trajectory of a Suicide Inhibitor in Human Indoleamine 2,3-Dioxygenase 1. Pham KN, Yeh SR. J. Am. Chem. Soc. 140 14538-14541 (2018)
  8. Conformational Plasticity in Human Heme-Based Dioxygenases. Pham KN, Lewis-Ballester A, Yeh SR. J Am Chem Soc 143 1836-1845 (2021)
  9. Implementation of the CYP Index for the Design of Selective Tryptophan-2,3-dioxygenase Inhibitors. Parr BT, Pastor R, Sellers BD, Pei Z, Jaipuri FA, Castanedo GM, Gazzard L, Kumar S, Li X, Liu W, Mendonca R, Pavana RK, Potturi H, Shao C, Velvadapu V, Waldo JP, Wu G, Yuen PW, Zhang Z, Zhang Y, Harris SF, Oh AJ, DiPasquale A, Dement K, La H, Goon L, Gustafson A, VanderPorten EC, Mautino MR, Liu Y. ACS Med Chem Lett 11 541-549 (2020)
  10. Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy. Yan D, Xu J, Wang X, Zhang J, Zhao G, Lin Y, Tan X. Int J Mol Sci 23 4668 (2022)
  11. Tryptophan 2,3-Dioxygenase Expression Identified in Murine Decidual Stromal Cells Is Not Essential for Feto-Maternal Tolerance. Hoffmann D, Dvorakova T, Schramme F, Stroobant V, Van den Eynde BJ. Front Immunol 11 601759 (2020)
  12. BF3-OEt2 Catalyzed C3-Alkylation of Indole: Synthesis of Indolylsuccinimidesand Their Cytotoxicity Studies. Shaikh IN, Rahim A, Faazil S, Adil SF, Assal ME, Hatshan MR. Molecules 26 2202 (2021)
  13. Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls. Mammoli A, Bianconi E, Ruta L, Riccio A, Bigiotti C, Souma M, Carotti A, Rossini S, Suvieri C, Pallotta MT, Grohmann U, Camaioni E, Macchiarulo A. Int J Mol Sci 23 3981 (2022)
  14. Design and Synthesis of Indoleamine 2,3-Dioxygenase 1 Inhibitors and Evaluation of Their Use as Anti-Tumor Agents. Wen H, Liu Y, Wang S, Wang T, Zhang G, Chen X, Li Y, Cui H, Lai F, Sheng L. Molecules 24 (2019)
  15. Discovery and Preclinical Evaluation of BMS-986242, a Potent, Selective Inhibitor of Indoleamine-2,3-dioxygenase 1. Cherney EC, Zhang L, Nara S, Zhu X, Gullo-Brown J, Maley D, Lin TA, Hunt JT, Huang C, Yang Z, Darienzo C, Discenza L, Ranasinghe A, Grubb M, Ziemba T, Traeger SC, Li X, Johnston K, Kopcho L, Fereshteh M, Foster K, Stefanski K, Fargnoli J, Swanson J, Brown J, Delpy D, Seitz SP, Borzilleri R, Vite G, Balog A. ACS Med Chem Lett 12 288-294 (2021)
  16. Discovery of Carbono(di)thioates as Indoleamine 2,3-Dioxygenase 1 Inhibitors. Kumazawa M, Tejima M, Fukuda M, Takeda S, Suzuki K, Mizumoto Y, Sato K, Waki M, Miyachi H, Asai A, Takikawa O, Hashimoto T, Ohno O, Matsuno K. ACS Med Chem Lett 12 211-216 (2021)
  17. Discovery of Icotinib-1,2,3-Triazole Derivatives as IDO1 Inhibitors. Mao LF, Wang YW, Zhao J, Xu GQ, Yao XJ, Li YM. Front Pharmacol 11 579024 (2020)
  18. Discovery of cyanopyridine scaffold as novel indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors through virtual screening and preliminary hit optimisation. Xu X, Ren J, Ma Y, Liu H, Rong Q, Feng Y, Wang Y, Cheng Y, Ge R, Li Z, Bian J. J Enzyme Inhib Med Chem 34 250-263 (2019)
  19. Exploration of good and bad structural fingerprints for inhibition of indoleamine-2,3-dioxygenase enzyme in cancer immunotherapy using Monte Carlo optimization and Bayesian classification QSAR modeling. Jain S, Bhardwaj B, Amin SA, Adhikari N, Jha T, Gayen S. J Biomol Struct Dyn 38 1683-1696 (2020)
  20. HFIP-promoted Michael reactions: direct para-selective C-H activation of anilines with maleimides. Li B, Mao Q, Zhou J, Liu F, Ye N. Org Biomol Chem 17 2242-2246 (2019)
  21. High-resolution structures of inhibitor complexes of human indoleamine 2,3-dioxygenase 1 in a new crystal form. Luo S, Xu K, Xiang S, Chen J, Chen C, Guo C, Tong Y, Tong L. Acta Crystallogr F Struct Biol Commun 74 717-724 (2018)
  22. Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold. Brant MG, Goodwin-Tindall J, Stover KR, Stafford PM, Wu F, Meek AR, Schiavini P, Wohnig S, Weaver DF. ACS Med Chem Lett 9 131-136 (2018)
  23. Preclinical PK investigation of a novel IDO1/TDO dual inhibitor-SHR9146 in mouse plasma and tissues by LC-MS/MS. Xiao M, Zhong K, Guo L, Li W, Wang X, Qiu Z, Hang T. Front Oncol 13 1191778 (2023)
  24. Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase. Pham KN, Lewis-Ballester A, Yeh SR. J Am Chem Soc 141 18771-18779 (2019)
  25. Temporary Intermediates of L-Trp Along the Reaction Pathway of Human Indoleamine 2,3-Dioxygenase 1 and Identification of an Exo Site. Mirgaux M, Leherte L, Wouters J. Int J Tryptophan Res 14 11786469211052964 (2021)


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