Tumor Immunotherapy Using A2A Adenosine Receptor Antagonists

Jinfeng Zhang, Wenzhong Yan, Wenwen Duan, Kurt Wüthrich, Jianjun Cheng, Jinfeng Zhang, Wenzhong Yan, Wenwen Duan, Kurt Wüthrich, Jianjun Cheng

Abstract

The A2A adenosine receptor (A2AAR) plays critical roles in human physiology and pathophysiology, which makes it an important drug target. Previous drug-discovery efforts targeting the A2AAR have been focused on the use of A2AAR antagonists for the treatment of Parkinson's disease. More recently, the A2AAR has attracted additional attention for its roles in immuno-oncology, and a number of A2AAR antagonists are currently used as lead compounds for antitumor drugs in both preclinical models and clinical trials. This review surveys recent advances in the development of A2AAR antagonists for cancer immunotherapy. The therapeutic potential of representative A2AAR antagonists is discussed based on both animal efficacy studies and clinical data.

Keywords: GPCR; Parkinson’s disease; cancer therapy; drug binding modes; immuno-oncology.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Adenosine-A2AAR signaling in the tumor microenvironment (the green circles represent adenosine molecules). ATP = adenosine triphosphate; AMP = adenosine monophosphate.
Figure 2
Figure 2
Chemical structures of A2AAR antagonists discussed in this chapter.
Figure 3
Figure 3
Binding modes of A2AAR with different antagonists. (A) ZM-241385; the key amino acid residues: Asn2536.55, Glu1695.30, Phe1685.29, Trp2466.48, and Ile2747.39 are identified (PDB ID: 3EML). (B) SYN-115; the key amino acid residues: Asn2536.55, Thr2566.58, Phe1685.29, and Trp2466.48 are identified (PDB ID: 5OLO). (C) AZD-4635; the key amino acid residues: Asn2536.55, Glu1695.30, Phe1685.29, and Trp2466.48 are identified (PDB ID: 6GT3). (D) V-2006; the key amino acid residues: Asn2536.55, Glu1695.30, Tyr91.35, Phe1685.29, and Trp2466.48 are identified (PDB ID: 5OLH). The A2AAR back bone is colored gray, and the amino acid side chains that interact with the ligands are shown as sticks and colored by element (carbon, yellow; nitrogen, blue; oxygen, red; sulfur, yellow; the side chain of Asn2536.55 is shown in a space filling presentation). The antagonists are shown as sticks and colored by element (carbon, green; nitrogen, blue; oxygen, red; sulfur, yellow). Polar contacts are presented as dashed lines, and water molecules are shown as red spheres.

References

    1. Fredholm B.B., IJzerman A.P., Jacobson K.A., Linden J., Müller C.E. International union of basic and clinical pharmacology. LXXXI. Nomenclature and classification of adenosine receptors—An update. Pharm. Rev. 2011;63:1–34. doi: 10.1124/pr.110.003285.
    1. Shook B.C., Jackson P.F. Adenosine A2A receptor antagonists and Parkinson’s disease. ACS Chem. Neurosci. 2011;2:555–567. doi: 10.1021/cn2000537.
    1. Klinger M., Freissmuth M., Nanoff C. Adenosine receptors: G protein-mediated signalling and the role of accessory proteins. Cell Signal. 2002;14:99–108. doi: 10.1016/S0898-6568(01)00235-2.
    1. Vijayan D., Young A., Teng M.W.L., Smyth M.J. Targeting immunosuppressive adenosine in cancer. Nat. Rev. Cancer. 2017;17:709–724. doi: 10.1038/nrc.2017.86.
    1. Jacobson K.A., Müller C.E. Medicinal chemistry of adenosine, P2Y and P2X receptors. Neuropharmacology. 2016;104:31–49. doi: 10.1016/j.neuropharm.2015.12.001.
    1. Waarde A., Dierckx R., Zhou X., Khanapur S., Tsukada H., Ishiwata K., Luurtsema G., de Vries E.F.J., Elsinga P.H. Potential therapeutic applications of adenosine A2A receptor ligands and opportunities for A2A receptor imaging. Med. Res. Rev. 2018;38:5–56. doi: 10.1002/med.21432.
    1. Garnock-Jones K.P., Curran M.P. Regadenoson. Am. J. Cardiovasc. Drugs. 2011;10:65–71. doi: 10.2165/10489040-000000000-00000.
    1. Hage F.G., Ghimire G., Lester D., McKay J., Bleich S., El-Hajj S., Iskandrian A.E. The prognostic value of regadenoson myocardial perfusion imaging. J. Nucl. Cardiol. 2015;22:1214–1221. doi: 10.1007/s12350-014-0050-y.
    1. Zheng J.Y., Zhang X.H., Zhen X.C. Development of adenosine A2A receptor antagonists for the treatment of Parkinson’s disease: A recent update and challenge. ACS Chem. Neurosci. 2019;10:783–791. doi: 10.1021/acschemneuro.8b00313.
    1. Jacobson K.A., Gao Z.G., Matricon P., Eddy M.T., Carlsson J. Adenosine A2A receptor antagonists: From caffeine to selective non-xanthines. Br. J. Pharmacol. 2020 doi: 10.1111/bph.15103. in press.
    1. Pinna A. Adenosine A2A receptor antagonists in Parkinson’s disease: Progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs. 2014;28:455–474. doi: 10.1007/s40263-014-0161-7.
    1. Dungo R., Deeks E.D. Istradefylline: First global approval. Drugs. 2013;73:875–882. doi: 10.1007/s40265-013-0066-7.
    1. Wolberg G., Zimmerman T.P., Hiemstra K., Winston M., Chu L. Adenosine inhibition of lymphocyte-mediated cytolysis: Possible role of cyclic adenosine monophosphate. Science. 1975;187:957–959. doi: 10.1126/science.167434.
    1. Blay J., White T.D., Hoskin D.W. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 1997;57:2602–2605.
    1. Ohta A., Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature. 2001;414:916–919. doi: 10.1038/414916a.
    1. Ohta A., Elieser Gorelik E., Prasad S.J., Ronchese F., Lukashev D., Wong M.K.K., Huang X., Caldwell S., Liu K., Smith P., et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl. Acad. Sci. USA. 2006;103:13132–13137. doi: 10.1073/pnas.0605251103.
    1. Hatfield S.M., Sitkovsky M. A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1alpha driven immunosuppression and improve immunotherapies of cancer. Curr. Opin. Pharmacol. 2016;29:90–96. doi: 10.1016/j.coph.2016.06.009.
    1. Mediavilla-Varela M., Castro J., Chiappori A., Noyes D., Hernandez D.C., Allard B., Stagg J., Antonia S.J. A novel antagonist of the immune checkpoint protein adenosine A2A receptor restores tumor-infiltrating lymphocyte activity in the context of the tumor microenvironment. Neoplasia. 2017;19:530–536. doi: 10.1016/j.neo.2017.02.004.
    1. Willingham S.B., Ho P.Y., Hotson A., Hill C., Piccione E.C., Hsieh J., Liu L., Buggy J.J., McCaffery I., Miller R.A. A2AR antagonism with CPI-444 induces antitumor responses and augments efficacy to anti-PD-L1 and anti-CTLA-4 in preclinical models. Cancer Immunol Res. 2018;6:1136–1149. doi: 10.1158/2326-6066.CIR-18-0056.
    1. Jaakola V., Griffith M.T., Hanson M.A., Cherezov V., Chien E.Y.T., Lane J.R., IJzerman A.P., Stevens R.C. The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science. 2008;322:1211–1216. doi: 10.1126/science.1164772.
    1. Xu F., Wu H., Katritch V., Han G.W., Jacobson K.A., Gao Z.G., Cherezov V., Stevens R.C. Structure of an agonist-bound human A2A adenosine receptor. Science. 2011;332:322–327. doi: 10.1126/science.1202793.
    1. Carpenter B., Nehme R., Warne T., Leslie A.G., Tate C.G. Structure of the adenosine A2A receptor bound to an engineered G protein. Nature. 2016;536:104–107. doi: 10.1038/nature18966.
    1. Susac L., Eddy M.T., Didenko T., Stevens R.C., Wüthrich K. A2A adenosine receptor functional states characterized by 19F-NMR. Proc. Natl. Acad. Sci. USA. 2018;115:12733–12738. doi: 10.1073/pnas.1813649115.
    1. Eddy M.T., Lee M.Y., Gao Z.G., White K.L., Didenko T., Horst R., Audet M., Stanczak P., McClary K.M., Han G.W., et al. Allosteric coupling of drug binding and intracellular signaling in the A2A adenosine receptor. Cell. 2018;172:68–80. doi: 10.1016/j.cell.2017.12.004.
    1. Hasko G., Linden J., Cronstein B., Pacher P. Adenosine receptors: Therapeutic aspects for inflammatory and immune diseases. Nat. Rev. Drug Discov. 2008;7:759–770. doi: 10.1038/nrd2638.
    1. Moesta A.K., Li X.Y., Smyth M.J. Targeting CD39 in cancer. Nat. Rev. Immunol. 2020 doi: 10.1038/s41577-020-0376-4.
    1. Colgan S.P., Eltzschig H.K., Eckle T., Thompson L.F. Physiological roles for ecto-5’-nucleotidase (CD73) Purinergic. Signal. 2006;2:351–360. doi: 10.1007/s11302-005-5302-5.
    1. Young A., Ngiow S.F., Madore J., Reinhardt J., Landsberg J., Chitsazan A., Rautela J., Bald T., Barkauskas D.S., Ahern E., et al. Targeting adenosine in BRAF-mutant melanoma reduces tumor growth and metastasis. Cancer Res. 2017;77:4684–4696. doi: 10.1158/0008-5472.CAN-17-0393.
    1. Kazemi M.H., Mohseni S.R., Hojjat-Farsangi M., Anvari E., Ghalamfarsa G., Mohammadi H., Jadidi-Niaragh F. Adenosine and adenosine receptors in the immunopathogenesis and treatment of cancer. J. Cell Physiol. 2018;233:2032–2057. doi: 10.1002/jcp.25873.
    1. Beavis P.A., Divisekera U., Paget C., Chow M.T., John L.B., Devaud C., Dwyer K., Stagg J., Smyth M.J., Darcy P.K. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc. Natl. Acad. Sci. USA. 2013;110:14711–14716. doi: 10.1073/pnas.1308209110.
    1. Ohta A., Kini R., Ohta A., Subramanian M., Madasu M., Sitkovsky M. The development and immunosuppressive functions of CD4+ CD25+ FoxP3+ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front. Immunol. 2012;3:190. doi: 10.3389/fimmu.2012.00190.
    1. Sorrentino C., Miele L., Porta A., Pinto A., Morello S. Myeloid-derived suppressor cells contribute to A2B adenosine receptor-induced VEGF production and angiogenesis in a mouse melanoma model. Oncotarget. 2015;6:27478–27489. doi: 10.18632/oncotarget.4393.
    1. Ahmada A., Ahmada S., Gloverb L., Millera S.M., Shannonc J.M., Guoa X., Franklind W.A., Bridgesc J.P., Schaacke J.B., Colganb S.P., et al. Adenosine A2A receptor is a unique angiogenic target of HIF-2α in pulmonary endothelial cells. Proc. Natl. Acad. Sci. USA. 2009;106:10684–10689. doi: 10.1073/pnas.0901326106.
    1. Kjaergaard J., Hatfield S., Jones G., Ohta A., Sitkovsky M. A2A adenosine receptor gene deletion or synthetic A2A antagonist liberate tumor-reactive CD8+ T Cells from tumor-induced immunosuppression. J. Immunol. 2018;201:782–791. doi: 10.4049/jimmunol.1700850.
    1. Congreve M., Brown G.A., Borodovsky A., Lamb M.L. Targeting adenosine A2A receptor antagonism for treatment of cancer. Expert Opin. Drug Discov. 2018;13:997–1003. doi: 10.1080/17460441.2018.1534825.
    1. Beavis P.A., Milenkovski N., Henderson M.A., John L.B., Allard B., Loi S., Kershaw M.H., Stagg J., Darcy P.K. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol. Res. 2015;3:506–517. doi: 10.1158/2326-6066.CIR-14-0211.
    1. Leone R.D., Sun I.M., Oh M.H., Sun I.H., Wen J., Englert J., Powell J.D. Inhibition of the adenosine A2A receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models. Cancer Immunol. Immunother. 2018;67:1271–1284. doi: 10.1007/s00262-018-2186-0.
    1. Gao Z.G., Jacobson K.A. A2B adenosine receptor and cancer. Int. J. Mol. Sci. 2019;20:5139. doi: 10.3390/ijms20205139.
    1. Leone R.D., Lo Y.C., Powell J.D. A2AR antagonists: Next generation checkpoint blockade for cancer immunotherapy. Comput. Struct. Biotechnol. J. 2015;13:265–272. doi: 10.1016/j.csbj.2015.03.008.
    1. Cekic C., Linden J. Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment. Cancer Res. 2014;74:7239–7249. doi: 10.1158/0008-5472.CAN-13-3581.
    1. Sepulveda C., Palomo I., Fuentes E. Role of adenosine A2B receptor overexpression in tumor progression. Life Sci. 2016;166:92–99. doi: 10.1016/j.lfs.2016.10.008.
    1. Walters M.J., Tan J.B., Becker A., Yi F.F., Park T., Leleti M.R., Rosen B., Sharif E., Debien L., Young S., et al. Characterization of the potent and selective A2AR antagonist AB928 for the treatment of cancer. Cancer Res. 2017;77:AM2017–AM4572.
    1. Mittal D., Young A., Stannard K., Yong M., Teng M.W., Allard B., Stagg J., Smyth M.J. Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 2014;74:3652–3658. doi: 10.1158/0008-5472.CAN-14-0957.
    1. Aoyama S., Ichimura M., Ikeda K., Ishii A., Kanda T., Koga K., Koike N., Kurokawa M., Kuwana Y., Mori A., et al. Progress in pursuit of therapeutic A2A antagonists: The adenosine A2A receptor selective antagonist KW-6002: Research and development toward a novel nondopaminergic therapy for Parkinson’s disease. Neurology. 2003;61:S97–S100. doi: 10.1212/01.wnl.0000095219.22086.31.
    1. Poucher S.M., Keddie J.R., Singh P., Stoggall S.M., Caulkett P.W.R., Jones G., Collis M.G. The in vitro pharmacology of ZM-241385, a potent, non-xanthine, A2A selective adenosine receptor antagonist. Br. J. Pharmacol. 1995;115:1096–1102. doi: 10.1111/j.1476-5381.1995.tb15923.x.
    1. De Zwart M., Vollinga R.C., Beukers M.W., Sleegers D.F., von Frijtag Drabbe Künze J.K., de Groote M., IJzerman A.P. Potent antagonists for the human adenosine A2B receptor. Derivatives of the triazolotriazine adenosine receptor antagonist ZM-241385 with high affinity. Drug Develop. Res. 1999;48:95–103. doi: 10.1002/(SICI)1098-2299(199911)48:3<95::AID-DDR1>;2-B.
    1. Ongini E., Dionisotti S., Irenius S.G.E., Fredholm B.B. Comparison of CGS-5943, ZM-241385 and SCH-58261 as antagonists at human adenosine receptors. Naunyn Schmiedeberg’s Arch. Pharmacol. 1999;359:7–10. doi: 10.1007/PL00005326.
    1. Neustadt B.R., Hao J., Lindo N., Greenlee W.J., Stamford A.W., Tulshian D., Ongini E., Hunter J., Monopoli A., Bertorelli R., et al. Potent, selective, and orally active adenosine A2A receptor antagonists: Arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines. Bioorg. Med. Chem. Lett. 2007;17:1376–1380. doi: 10.1016/j.bmcl.2006.11.083.
    1. Flohr A., Moreau J., Poli S.M., Riemer C., Steward L. 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide. 20,050,261,289. US Patent. 2005 Nov 24;
    1. Borodovsky A., Wang Y., Ye M., Shaw J.C., Sachsenmeier K.F., Deng N., DelSignore K.J., Fretland A.J., Clarke J.D., Goodwin R.J., et al. Abstract 5580: Preclinical pharmacodynamics and antitumor activity of AZD-4635, a novel adenosine 2A receptor inhibitor that reverses adenosine mediated T cell suppression. AACR Annu. Meet. 2017 doi: 10.1158/1538-7445.AM2017-5580.
    1. Gillespie R.J., Bamford S.J., Botting R., Comer M., Denny S., Gaur S., Griffin M., Jordan A.M., Knight A.R., Lerpiniere J., et al. Antagonists of the human A2A adenosine receptor. 4. Design, synthesis, and preclinical evaluation of 7-aryltriazolo[4,5-d]pyrimidines. J. Med. Chem. 2009;52:33–47. doi: 10.1021/jm800961g.
    1. Uustare A., Vonk A., Terasmaa A., Fuxe K., Rinken A. Kinetic and functional properties of [3H] ZM-241385, a high affinity antagonist for adenosine A2A receptors. Life Sci. 2005;76:1513–1526. doi: 10.1016/j.lfs.2004.10.027.
    1. Jeon S.J., Rhee S.Y., Ryu J.H., Cheong J.H., Kwon K., Yang S.I., Park S.H., Lee J., Kim H.Y., Han S.H., et al. Activation of adenosine A2A receptor up-regulates BDNF expression in rat primary cortical neurons. Neurochem. Res. 2011;36:2259–2269. doi: 10.1007/s11064-011-0550-y.
    1. Da Rocha Lapa F., da Silva M.D., de Almeida Cabrini D., Santos A.R. Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy: Evidence for the role of adenosine A2 receptors. Purinergic Signal. 2012;8:693–704. doi: 10.1007/s11302-012-9299-2.
    1. Iannone R., Miele L., Maiolino P., Pinto A., Morello S. Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model. Am. J. Cancer. Res. 2014;4:172–181. doi: 10.3727/096504014X13890370410249.
    1. Keddie J.R., Poucher S.M., Shaw G.R., Brooks R., Collis M.G. In vivo characterisation of ZM-241385, a selective adenosine A2A receptor antagonist. Eur. J. Pharmacol. 1996;301:107–113. doi: 10.1016/0014-2999(96)00020-9.
    1. Yang M., Soohoo D., Soelaiman S., Kalla R., Zablocki J., Chu N., Leung K., Yao L., Diamond I., Belardinelli L., et al. Characterization of the potency, selectivity, and pharmacokinetic profile for six adenosine A2A receptor antagonists. Naunyn Schmiedebergs Arch. Pharmacol. 2007;375:133–144. doi: 10.1007/s00210-007-0135-0.
    1. Kiselgof E., Tulshian D.B., Arik L., Zhang H., Fawzi A. 6-(2-Furanyl)-9H-purin-2-amine derivatives as A2A adenosine antagonists. Bioorg. Med. Chem. Lett. 2005;15:2119–2122. doi: 10.1016/j.bmcl.2005.02.031.
    1. Loi S., Pommey S., Haibe-Kains B., Beavis P.A., Darcy P.K., Smyth M.J., Stagg J. CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc. Natl. Acad. Sci. USA. 2013;110:11091–11096. doi: 10.1073/pnas.1222251110.
    1. Hodgson R.A., Bertorelli R., Varty G.B., Lachowicz J.E., Forlani A., Fredduzzi S., Cohen-Williams M.E., Higgins G.A., Impagnatiello F., Nicolussi E., et al. Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH-412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in rodent models of movement disorders and depression. J. Pharmacol. Exp. Ther. 2009;330:294–303. doi: 10.1124/jpet.108.149617.
    1. Nunez F., Taura J., Camacho J., Lopez-Cano M., Fernandez-Duenas V., Castro N., Castro J., Ciruela F. PBF509, an adenosine A2A receptor antagonist with efficacy in rodent models of movement disorders. Front. Pharmacol. 2018;9:1200. doi: 10.3389/fphar.2018.01200.
    1. Chiappori A., Williams C., Creelan B., Tanvetyanon T., Gray J., Haura E., Chen D.T., Thapa R., Beg A., Boyle T., et al. Phase I/II study of the A2AR antagonist NIR178 (PBF-509), an oral immunotherapy, in patients (pts) with advanced NSCLC. J. Thorac. Oncol. 2018;13 doi: 10.1016/j.jtho.2018.08.747.
    1. Hauser R.A., Olanow C.W., Kieburtz K.D., Pourcher E., Docu-Axelerad A., Lew M., Kozyolkin O., Neale A., Resburg C., Meya U., et al. Tozadenant (SYN115) in patients with Parkinson’s disease who have motor fluctuations on levodopa: A phase 2b, double-blind, randomised trial. Lancet. Neurol. 2014;13:767–776. doi: 10.1016/S1474-4422(14)70148-6.
    1. Bamford S.J., Gillespie R.J., Todd R.S. Triazolo[4,5-d]pyramidine derivatives and their use as purine receptor antagonists. WO2,009,156,737. 2009 Dec 30;
    1. Schindler U., Seitz L., Ashok D., Piovesan D., Tan J., DiRenzo D., Yin F., Leleti M., Rosen B., Miles D., et al. AB928, a dual antagonist of the A2AR and A2BR adenosine receptors, leads to greater immune activation and reduced tumor growth when combined with chemotherapy. Eur. J. Cancer. 2018;92:S14–S15. doi: 10.1016/j.ejca.2018.01.037.
    1. Seitz L., Jin L., Leleti M., Ashok D., Jeffrey J., Rieger A., Tiessen R.G., Arold G., Tan J.B.L., Powers J.P., et al. Safety, tolerability, and pharmacology of AB928, a novel dual adenosine receptor antagonist, in a randomized, phase 1 study in healthy volunteers. Investig. New Drugs. 2019;37:711–721. doi: 10.1007/s10637-018-0706-6.
    1. Crosignani S., Dickinson P., de Matas M., Houthuys E.J.K.H., Marillier R.G., Martinoli C., de Henau O., Deriessens G. Thiocarbamate derivatives as A2A inhibitors, pharmaceutical composition thereof and combinations with anticancer agents. WO2,020,053,263. 2020 Mar 19;
    1. iTeos Therapeutics. [(accessed on 14 August 2020)]; Available online:
    1. Dore A.S., Robertson N., Errey J.C., Ng I., Hollenstein K., Tehan B., Hurrell E., Bennett K., Congreve M., Magnani F., et al. Structure of the adenosine A2A receptor in complex with ZM-241385 and the xanthines XAC and caffeine. Structure. 2011;19:1283–1293. doi: 10.1016/j.str.2011.06.014.
    1. Rucktooa P., Cheng R.K.Y., Segala E., Geng T., Errey J.C., Brown G.A., Cooke R.M., Marshall F.H., Dore A.S. Towards high throughput GPCR crystallography: In meso soaking of adenosine A2A receptor crystals. Sci. Rep. 2018;8:41. doi: 10.1038/s41598-017-18570-w.
    1. Congreve M., Andrews S.P., Dore A.S., Hollenstein K., Hurrell E., Langmead C.J., Mason J.S., Ng I.W., Tehan B., Zhukov A., et al. Discovery of 1,2,4-triazine derivatives as adenosine A2A antagonists using structure based drug design. J. Med. Chem. 2012;55:1898–1903. doi: 10.1021/jm201376w.
    1. Guo D., Xia L., van Veldhoven J.P., Hazeu M., Mocking T., Brussee J., Ijzerman A.P., Heitman L.H. Binding kinetics of ZM-241385 derivatives at the human adenosine A2A receptor. Chem. Med. Chem. 2014;9:752–761. doi: 10.1002/cmdc.201300474.
    1. Sun B., Bachhawat P., Chu M.L., Wood M., Ceska T., Sands Z.A., Mercier J., Lebon F., Kobilka T.S., Kobilka B.K. Crystal structure of the adenosine A2A receptor bound to an antagonist reveals a potential allosteric pocket. Proc. Natl. Acad. Sci. USA. 2017;114:2066–2071. doi: 10.1073/pnas.1621423114.
    1. Igonet S., Raingeval C., Cecon E., Pucic-Bakovic M., Lauc G., Cala O., Baranowski M., Perez J., Jockers R., Krimm I., et al. Enabling STD-NMR fragment screening using stabilized native GPCR: A case study of adenosine receptor. Sci. Rep. 2018;8:8142. doi: 10.1038/s41598-018-26113-0.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa