药学学报, 2021, 56(5): 1265-1278
引用本文:
董俊敏, 刘站柱*. 基于靶标IDO1、TDO的抑制剂研究进展[J]. 药学学报, 2021, 56(5): 1265-1278.
DONG Jun-min, LIU Zhan-zhu*. Advances in research on inhibitors based on targets:IDO1 and TDO[J]. Acta Pharmaceutica Sinica, 2021, 56(5): 1265-1278.

基于靶标IDO1、TDO的抑制剂研究进展
董俊敏, 刘站柱*
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
摘要:
吲哚胺2,3-双加氧酶1(IDO1)和色氨酸2,3-双加氧酶(TDO)催化色氨酸代谢的第一步也是限速步骤,与肿瘤免疫耐受和患者的不良预后相关,已经成为肿瘤免疫治疗的重要靶标。到目前为止,有9个IDO1抑制剂、3个IDO1/TDO双靶点抑制剂进入临床试验。本篇综述从药物化学角度总结了IDO1抑制剂、TDO抑制剂、IDO1/TDO双重抑制剂的研究进展。
关键词:    吲哚胺2,3-双加氧酶1      色氨酸2,3-双加氧酶      免疫治疗      抑制剂      构效关系     
Advances in research on inhibitors based on targets:IDO1 and TDO
DONG Jun-min, LIU Zhan-zhu*
State Key Laboratory of Bioactive Substance and Function of Nature Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) catalyze the initial and rate limiting step in the catabolism of tryptophan, which is related to tumor immune tolerance and poor prognosis in patients. In this regard, two enzymes have become important therapeutic targets for tumor immunotherapy. So far, nine IDO1 inhibitors and three IDO1/TDO dual inhibitors have entered clinical trials. This review summarizes the research progress of IDO1 inhibitors, TDO inhibitors and IDO1/TDO dual inhibitors from the perspective of medicinal chemistry.
Key words:    indoleamine-2,3-dioxygenase 1    tryptophan-2,3-dioxygenase    immunotherapy    inhibitor    structure-activity relationship   
收稿日期: 2020-11-03
DOI: 10.16438/j.0513-4870.2020-1691
基金项目: 中国医学科学院医学与健康科技创新工程(2016-I2M-3-009);“十三五”新药创制重大专项(2018ZX09711-001-005-014,001-005)
通讯作者: 刘站柱,Tel:86-10-63165253,E-mail:liuzhanzhu@imm.ac.cn
Email: liuzhanzhu@imm.ac.cn
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参考文献:
[1] Takikawa O. Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolism[J]. Biochem Biophys Res Commun, 2005, 338:12-19.
[2] Löb S, Königsrainer A, Rammensee HG, et al. Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy:can we see the wood for the trees?[J]. Nat Rev, 2009, 9:445-452.
[3] Delfourne E. Marine natural products and other derivatives as potent indoleamine 2,3-dioxygenase inhibitors[J]. Mini Rev Med Chem, 2012, 12:988-996.
[4] Brochez L, Chevolet I, Kruse V. The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy[J]. Eur J Cancer, 2017, 76:167-182.
[5] Weng TW, Qiu XQ, Wang JB, et al. Recent discovery of indoleamine-2,3-dioxygenase 1 inhibitors targeting cancer immunotherapy[J]. Eur J Med Chem, 2018, 143:656-669.
[6] Batabyal D, Yeh SR. Human tryptophan dioxygenase:a comparison to indoleamine 2,3-dioxygenase[J]. J Am Chem Soc, 2007, 129:15690-15701.
[7] Qian S, Zhang M, Chen QL, et al. IDO as a drug target for cancer immunotherapy:recent developments in IDO inhibitors discovery[J]. RSC Adv, 2016, 6:7575-7581.
[8] Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer:beyond IDO and tryptophan depletion[J]. Cancer Res, 2012, 72:5435-5440.
[9] Pilotte L, Larrieu P, Stroobant V, et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase[J]. Proc Natl Acad Sci U S A, 2012, 109:2497-2502.
[10] Shin I, Ambler BR, Wherritt D, et al. O-atom transfer in heme-based tryptophan dioxygenase:role of substrate ammonium in epoxide ring opening[J]. J Am Chem Soc, 2018, 140:4372-4379.
[11] Yu CP, Song YL, Zhu ZM, et al. Targeting TDO in cancer immunotherapy[J]. Med Oncol, 2017, 34:73.
[12] Wu H, Gong JP, Liu Y. Indoleamine 2, 3-dioxygenase regulation of immune response (review)[J]. Mol Med Rep, 2018, 17:4867-4873.
[13] Song H, Park H, Kim YS, et al. L-Kynurenine-induced apoptosis in human NK cells is mediated by reactive oxygen species[J]. Int Immunopharm, 2011, 11:932-938.
[14] Sugimoto H, Oda S, Otsuki T, et al. Crystal structure of human indoleamine 2,3-dioxygenase:catalytic mechanism of O2 incorporation by a heme-containing dioxygenase[J]. Proc Natl Acad Sci U S A, 2006, 103:2611-2616.
[15] Forouhar F, Anderson JR, Mowat CG, et al. Molecular insights into substrate recognition and catalysis by tryptophan 2,3-dioxygenase[J]. Proc Natl Acad Sci U S A, 2007, 104:473-478.
[16] Zhang Y, Kang SA, Mukherjee T, et al. Crystal structure and mechanism of tryptophan 2,3-dioxygenase, a heme enzyme involved in tryptophan catabolism and in quinolinate biosynthesis[J]. Biochemistry, 2007, 46:145-155.
[17] Huang W, Gong Z, Li J, et al. Crystal structure of drosophila melanogaster tryptophan 2,3-dioxygenase reveals insights into substrate recognition and catalytic mechanism[J]. J Struct Biol, 2013, 181:291-299.
[18] Meng B, Wu D, Gu J, et al. Structural and functional analyses of human tryptophan 2,3-dioxygenase[J]. Proteins, 2014, 82:3210-3216.
[19] Zhu MT, Dancsok AR, Nielsen TO. Indoleamine dioxygenase inhibitors:clinical rationale and current development[J]. Curr Oncol Rep, 2019, 21:2.
[20] Uyttenhove C, Pilotte L, Theate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase[J]. Nat Med, 2003, 9:1269-1274.
[21] Rohrig UF, Majjigapu SR, Vogel P, et al. Challenges in the discovery of indoleamine 2,3-dioxygenase 1(IDO1) inhibitors[J]. J Med Chem, 2015, 58:9421-9437.
[22] Du TT, Lai FF, Chen XG. Research progress of indoleamine 2,3-dioxygenase 1 in tumor immunotherapy[J]. Acta Pharm Sin (药学学报), 2018, 53:1271-1278.
[23] Zhang XY, Cui GD, Xu BL. The research progress of indoleamine 2,3-dioxygenase 1(IDO1) inhibitors[J]. Acta Pharm Sin (药学学报), 2018, 53:1784-1796
[24] Kumar S, Waldo JP, Jaipuri FA, et al. Discovery of clinical candidate (1R,4R)-4-((R)-2-((S)-6-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a potent and selective inhibitor of indoleamine 2,3-dioxygenase 1[J]. J Med Chem, 2019, 62:6705-6733.
[25] Peng YH, Ueng SH, Tseng CT, et al. Important hydrogen bond networks in indoleamine 2,3-dioxygenase 1(IDO1) inhibitor design revealed by crystal structures of imidazoleisoindole derivatives with IDO1[J]. J Med Chem, 2016, 59:282-293.
[26] Tu WY, Yang FL, Xu GJ, et al. Discovery of imidazoisoindole derivatives as highly potent and orally active indoleamine-2,3-dioxygenase inhibitors[J]. ACS Med Chem Lett, 2019, 10:949-953.
[27] Serafini M, Torre E, Aprile S, 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]. J Med Chem, 2020, 63:3047-3065.
[28] Tojo S, Kohno T, Tanaka T, et al. Crystal structures and structure-activity relationships of imidazothiazole derivatives as IDO1 inhibitors[J]. ACS Med Chem Lett, 2014, 5:1119-1123.
[29] Griglio A, Torre E, Serafini M, et al. A multicomponent approach in the discovery of indoleamine 2, 3-dioxygenase 1 inhibitors:synthesis, biological investigation and docking studies[J]. Bioorg Med Chem Lett, 2018, 28:651-657.
[30] Serafini M, Torre E, Aprile S, et al. Synthesis, docking and biological evaluation of a novel class of imidazothiazoles as IDO1 inhibitors[J]. Molecules, 2019, 24:1874.
[31] Yue EW, Sparks R, Polam P, et al. INCB24360(epacadostat), a highly potent and selective indoleamine-2,3-dioxygenase 1(IDO1) inhibitor for immunooncology[J]. ACS Med Chem Lett, 2017, 8:486-491.
[32] Chen SL, Guo W, Liu XH, et al. Design, synthesis and antitumor study of a series of N-cyclic sulfamoylaminoethyl substituted 1,2,5-oxadiazol-3-amines as new indoleamine 2,3-dioxygenase 1(IDO1) inhibitors[J]. Eur J Med Chem, 2019, 179:38-55.
[33] Song XH, Sun P, Wang J, et al. Design, synthesis, and biological evaluation of 1,2,5-oxadiazole-3-carboximidamide derivatives as novel indoleamine-2,3-dioxygenase 1 inhibitors[J]. Eur J Med Chem, 2020, 189:112059.
[34] Steeneck C, Kinzel O, Anderhub S, et al. Discovery of hydroxyamidine based inhibitors of IDO1 for cancer immunotherapy with reduced potential for glucuronidation[J]. ACS Med Chem Lett, 2020, 11:179-187
[35] Du QM, Feng X, Wang YN, et al. Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer[J]. Eur J Med Chem, 2019, 182:111629.
[36] Paul S, Roy A, Deka SJ, et al. Nitrobenzofurazan derivatives of N'-hydroxyamidines as potent inhibitors of indoleamine-2,3-dioxygenase 1[J]. Eur J Med Chem, 2016, 121:364-375.
[37] Markwalder JA, Seitz SP, Blat Y, et al. Identification and optimization of a novel series of indoleamine 2,3-dioxygenase inhibitors[J]. Bioor Med Chem Lett, 2017, 27:582-585.
[38] Williams DK, Markwalder DA, Balog AJ, et al. Development of a series of novel o-phenylenediamine-based indoleamine 2,3-dioxygenase 1(IDO1) inhibitors[J]. Bioorg Med Chem Lett, 2018, 28:732-736.
[39] Cai S, Yang XJ, Chen P, et al. Design, synthesis and biological evaluation of bicyclic carboxylic acid derivatives as IDO1 inhibitors[J]. Bioorg Chem, 2020, 94:103356.
[40] Blunt CE, Torcuk C, Liu Y, et al. Synthesis and intracellular redox cycling of natural quinones and their analogues and identification of indoleamine-2,3-dioxygenase (IDO) as potential target for anticancer activity[J]. Angew Chem Int Ed, 2015, 54:8740-8745.
[41] Pan DY, Zhang XX, Zheng HZ, et al. Novel anthraquinone derivatives as inhibitors of protein tyrosine phosphatases and indoleamine 2,3-dioxygenase 1 from the deep-sea derived fungus Alternaria tenuissima DFFSCS013[J]. Org Chem Front, 2019, 6:3252-3258.
[42] Carvalho C, Siegel D, Inman M, et al. Benzofuranquinones as inhibitors of indoleamine 2,3-dioxygenase (IDO). Synthesis and biological evaluation[J]. Org Biomol Chem, 2014, 12:2663-2674.
[43] Pan LK, Zheng Q, Chen Y, et al. Design, synthesis and biological evaluation of novel naphthoquinone derivatives as IDO1 inhibitors[J]. Eur J Med Chem, 2018, 157:423-436.
[44] Cady SG, Sono M. 1-Methyl-DL-tryptophan, beta-(3-benzofuranyl)-DL-alanine (the oxygen analog of tryptophan), and beta-[3-benzo(b-)thienyl]-DL-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase[J]. Arch Biochem Biophys, 1991, 291:326-333.
[45] Nakashima H, Uto Y, Nakata E, et al. Synthesis and biological activity of 1-methyl-tryptophan-tirapazamine hybrids as hypoxia-targeting indoleamine 2,3-dioxygenase inhibitors[J]. Bioorg Med Chem, 2008, 16:8661-8669.
[46] Awuah SG, Zheng YR, Bruno PM. A Pt (IV) pro-drug preferentially targets indoleamine-2,3-dioxygenase, providing enhanced ovarian cancer immuno-chemotherapy[J]. J Am Chem Soc, 2015, 137:14854-14857.
[47] Crosignani S, Bingham P, Bottemanne P, 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 (EOS2-00271/PF-06840003) and its characterization as a potential clinical candidate[J]. J Med Chem, 2017, 60:9617-9629.
[48] Beck HP, Jaen JC, Osipov M, et al. Immunoregulatory agents:US, 059311[P]. 2016-05-12.
[49] Nelp MT, Kates PA, Hunt JT, et al. Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form[J]. Proc Natl Acad Sci U S A, 2018, 115:3249-3254.
[50] Lin SY, Yeh TK, Kuo CC, et al. Phenyl benzenesulfoylhydrazides exhibit selective indoleamine 2,3-dioxygenase inhibition with potent in vivo pharmacodynamic activity and antitumor efficacy[J]. J Med Chem, 2016, 59:419-430.
[51] Malachowski WP, Winters M, DuHadaway JB, et al. O-Alkylhydroxy-lamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1[J]. Eur J Med Chem, 2016, 108:564-576.
[52] Panda S, Roy A, Deka SJ, et al. Fused heterocyclic compounds as potent indoleamine-2,3-dioxygenase 1 inhibitors[J]. ACS Med Chem Lett, 2016, 7:1167-1172.
[53] Xu X, Ren J, Ma YH, et al. Discovery of cyanopyridine scaffold as novel indoleamine-2,3 dioxygenase 1(IDO1) inhibitors through virtual screening and preliminary hit optimization[J]. J Enzyme Inhibit Med Chem, 2019, 34:250-263.
[54] Opitz CA, Litzenburger UM, Sahm F, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor[J]. Nature, 2011, 478:197-203.
[55] Civen M, Knox WE. The specificity of tryptophan analogues as inducers, substrates, inhibitors, and stabilizers of liver tryptophan pyrrolase[J]. J Biol Chem, 1960, 235:1716-1718.
[56] Frieden E, Westmark GW, Schor JM. Inhibition of tryptophan pyrrolase by serotonin, epinephrine and tryptophan analogs[J]. Arch Biochem Biophys, 1961, 92:176-182.
[57] Eguchi N, Watanabe Y, Kawanishi K, et al. Inhibition of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase by beta-carboline and indole derivatives[J]. Arch Biochem Biophys, 1984, 232:602-609.
[58] Salter M, Hazelwood R, Pogson CI, et al. The effects of a novel and selective inhibitor of tryptophan 2,3-dioxygenase on tryptophan and serotonin metabolism in the rat[J]. J Biochem Pharmacol, 1995, 49:1435-1442.
[59] Dolusic E, Larrieu P, Moineaux L, et al. Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators[J]. J Med Chem, 2011, 54:5320-5334.
[60] Pilottea L, Larrieua P, Stroobanta V, et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase[J]. J Proc Natl Acad Sci U S A, 2012, 109:2497-2502.
[61] Abdel-Magid AF. Targeting the inhibition of tryptophan 2,3-dioxygenase (TDO-2) for cancer treatment[J]. ACS Med Chem Lett, 2017, 8:11-13.
[62] Wu JS, Lin SY, Liao FY, et al. Identification of substituted naphthotriazolediones as novel tryptophan 2,3-dioxygenase (TDO) inhibitors through structure based virtual screening[J]. J Med Chem, 2015, 58:7807-7819.
[63] Hua SX, Chen FH, Wang XY, et al. Pt (IV) hybrids containing a TDO inhibitor serve as potential anticancer immunomodulators[J]. J Inorg Biochem, 2019, 195:130-140.
[64] Pei ZH, Mendonca R, Gazzard L, et al. Aminoisoxazoles as potent inhibitors of tryptophan 2,3-dioxygenase 2(TDO2)[J]. ACS Med Chem Lett, 2018, 9:417-421.
[65] Frieden E, Westmark GW, Schor JM. Inhibition of tryptophan pyrrolase by serotonin, epinephrine and tryptophan analogs[J]. Arch Biochem Biophys, 1961, 92:176-182.
[66] Pantouris G, Mowat GG. Antitumor agents as inhibitors of tryptophan 2,3-dioxygenase[J]. Biochem Biophys Res Commun, 2014, 443:28-31.
[67] Zhang SN, Qi FF, Fang X, et al. Tryptophan 2,3-dioxygenase inhibitory activities of tryptanthrin derivatives[J]. Eur J Med Chem, 2018, 160:133-145.
[68] Parr BT, Pastor R, Sellers BD, et al. Implementation of the CYP index for the design of selective tryptophan-2,3-dioxygenase inhibitors[J]. ACS Med Chem Lett, 2020, 11:541-549.
[69] Muller AJ, Manfredi MG, Zakharia Y, et al. Inhibiting IDO pathways to treat cancer:lessons from the ECHO-301 trial and beyond[J]. Immunopathol, 2019, 41:41-48.
[70] Cui GN, Lai FF, Wang XY, et al. Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as IDO1/TDO dual inhibitors[J]. Eur J Med Chem, 2020, 188:111985.
[71] Yang LL, Chen Y, He JL, et al. 4,6-Substituted-1H-indazoles as potent IDO1/TDO dual inhibitors[J]. Bioorg Med Chem, 2019, 27:1087-1098.
[72] Yang D, Zhang SN, Fang X, et al. N-Benzyl/aryl substituted tryptanthrin as dual inhibitors of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase[J]. J Med Chem, 2019, 62:9161-9174.
[73] Lia YY, Zhang SN, Wang R, et al. Synthesis of novel tryptanthrin derivatives as dual inhibitors of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase[J]. Bioorg Med Chem Lett, 2020, 30:127-159.
[74] Feng X, Shen P, Wang Y. Synthesis and in vivo antitumor evaluation of an orally active potent phosphonamidate derivative targeting IDO1/IDO2/TDO[J]. Biochem Pharmacol, 2019, 168:214-223.
[75] Guo W, Yao S, Sun P, et al. Discovery and characterization of natural products as novel indoleamine 2,3-dioxygenase 1 inhibitors through high-throughput screening[J]. Acta Pharmacol Sin, 2020, 41:423-431.
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24.陈佩林;彭司勋;杨祯祥.缬(丙)-酪和缬-酪-酪肽类化合物的合成和生物活性[J]. 药学学报, 1992,27(12): 895-902
25.王明亮;纪庆娥.二氢吲哚类化合物的合成及其抑酶活性[J]. 药学学报, 1991,26(2): 103-110
26.李仁利;方肇霞.二氢叶酸还原酶抑制剂:5-取代苄基-2,4-二氨基嘧啶类化合物选择性作用的研究[J]. 药学学报, 1986,21(10): 753-760