Small-molecule CD73 inhibitors for the immunotherapy of cancer: a patent and literature review (2017–present)

References

• Bogan KL, Brenner C. 5′-Nucleotidases and their new roles in NAD+ and phosphate metabolism. New J Chem. 2010;34(5):845–853.
   Web of Science ®Google Scholar
• Strater N. Ecto-5’-nucleotidase: structure function relationships. Purinergic Signalling. 2006;2(2):343–350.
   PubMedGoogle Scholar
• Burnstock G, Verkhratsky A. Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death. Cell Death Dis. 2010;1:e9.
   PubMed Web of Science ®Google Scholar
• Bianchi V, Pontis E, Reichard P. Interrelations between substrate cycles and de novo synthesis of pyrimidine deoxyribonucleoside triphosphates in 3T6 cells. Proc Natl Acad Sci U S A. 1986;83(4):986–990.
   PubMed Web of Science ®Google Scholar
• Allard B, Turcotte M, Stagg J. CD73-generated adenosine: orchestrating the tumor-stroma interplay to promote cancer growth. J Biomed Biotechnol. 2012;2012:485156.
   PubMedGoogle Scholar
• Allard D, Chrobak P, Allard B, et al. Targeting the CD73-adenosine axis in immuno-oncology. Immunol Lett. 2019;205:31–39.
   PubMed Web of Science ®Google Scholar
• Knöfel T, Sträter N. Mechanism of hydrolysis of phosphate esters by the dimetal center of 5′-nucleotidase based on crystal structures. J Mol Biol. 2001;309(1):239–254.
   PubMed Web of Science ®Google Scholar
• Knapp K, Zebisch M, Pippel J, et al. Crystal structure of the human Ecto-5′-Nucleotidase (CD73): insights into the regulation of purinergic signaling. Structure. 2012;20(12):2161–2173.
   PubMed Web of Science ®Google Scholar
• Zimmermann H. 5′-Nucleotidase: molecular structure and functional aspects. Biochem J. 1992;285(2):345–365.
   PubMedGoogle Scholar
• Zhang B. CD73: a novel target for cancer immunotherapy: figure 1. Cancer Res. 2010;70(16):6407–6411.
   PubMed Web of Science ®Google Scholar
• Zimmermann H, Zebisch M, Strater N. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal. 2012;8:437–502.
   PubMed Web of Science ®Google Scholar
• Burnstock G. Purine and pyrimidine receptors. Cell Mol Life Sci. 2007;64(12):1471–1483.
   PubMed Web of Science ®Google Scholar
• Castrop H, Huang Y, Hashimoto S, et al. Impairment of tubuloglomerular feedback regulation of GFR in ecto-5′-nucleotidase/CD73–deficient mice. J Clin Invest. 2004;114(5):634–642.
   PubMed Web of Science ®Google Scholar
• Koszalka P, Ozuyaman B, Huo Y, et al. Targeted Disruption of cd73/Ecto-5′-Nucleotidase alters thromboregulation and augments vascular inflammatory response. Circ Res. 2004;95(8):814–821.
   PubMed Web of Science ®Google Scholar
• Bhattarai S, Pippel J, Scaletti E, et al., 2-Substituted α,β-Methylene-ADP Derivatives: potent Competitive Ecto-5′-nucleotidase (CD73) inhibitors with variable binding modes. J Med Chem. 63(6): 2941–2957. 2020.
   PubMed Web of Science ®Google Scholar
• Antonioli L, Fornai M, Blandizzi C, et al. Adenosine signaling and the immune system: when a lot could be too much. Immunol Lett. 2019;205:9–15.
   PubMed Web of Science ®Google Scholar
• Stagg J, Divisekera U, McLaughlin N, et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci U S A. 2010;107(4):1547–1552.
   PubMed Web of Science ®Google Scholar
• Vijayan D, Young A, Teng MWL, et al. Erratum: targeting immunosuppressive adenosine in cancer. Nat Rev Cancer. 2017;17(12):765.
   PubMed Web of Science ®Google Scholar
• Hay CM, Sult E, Huang Q, et al. Targeting CD73 in the tumor microenvironment with MEDI9447. Oncoimmunology. 2016;5(8):e1208875.
   PubMed Web of Science ®Google Scholar
• Geoghegan JC, Diedrich G, Lu X, et al. Inhibition of CD73 AMP hydrolysis by a therapeutic antibody with a dual, non-competitive mechanism of action. MAbs. 2016;8(3):454–467.
   PubMed Web of Science ®Google Scholar
• Bowman CE, Da Silva RG, Pham A, et al. An Exceptionally Potent Inhibitor of Human CD73. Biochemistry. 2019;58(31):3331–3334.
   PubMed Web of Science ®Google Scholar
• Baqi Y. Ecto-nucleotidase inhibitors: recent developments in drug discovery. Mini Rev Med Chem. 2015;15(1):21–33.
   PubMed Web of Science ®Google Scholar
• Al-Rashida M, Qazi SU, Batool N, et al. Ectonucleotidase inhibitors: a patent review (2011-2016). Expert Opin Ther Pat. 2017;27(12):1291–1304.
   PubMed Web of Science ®Google Scholar
• Baqi Y, Lee SY, Iqbal J, et al. Development of potent and selective inhibitors of ecto −5′-nucleotidase based on an anthraquinone scaffold. J Med Chem. 2010;53(5):2076–2086.
   PubMed Web of Science ®Google Scholar
• Bhattarai S, Freundlieb M, Pippel J, et al. α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: development of potent and selective ecto-5ʹ-Nucleotidase (CD73) Inhibitors. J Med Chem. 2015;58(15):6248–6263.
   PubMed Web of Science ®Google Scholar
• Junker A, Renn C, Dobelmann C, et al. Structure–Activity Relationship of Purine and Pyrimidine Nucleotides as Ecto-5′-Nucleotidase (CD73) Inhibitors. J Med Chem. 2019;62(7):3677–3695.
   PubMed Web of Science ®Google Scholar
• Nocentini A, Angeli A, Carta F, et al. Reconsidering anion inhibitors in the general context of drug design studies of modulators of activity of the classical enzyme carbonic anhydrase. J Enzyme Inhib Med Chem. 2021 Dec;36(1):561–580.
   PubMed Web of Science ®Google Scholar
• Gonzalez MM, Vila AJ. An elusive task: a clinically useful inhibitor of metallo-β-lactamases. Top Med Chem. 2017;22:1–34.
   Google Scholar
• Ambrose EA. Botulinum neurotoxin, tetanus toxin, and anthrax lethal factor countermeasures. Top Med Chem. 2017;22:47–68.
   Google Scholar
• Sconauer E, Brandstetter H. Inhibition and activity regulation of bacterial collagenases. Top Med Chem. 2017;22:69–94.
   Google Scholar
• Bhattarai S, Pippel J, Meyer A, et al. X-Ray Co-Crystal Structure Guides the Way to Subnanomolar Competitive Ecto-5′-Nucleotidase (CD73) Inhibitors for Cancer Immunotherapy. Adv.Therap 2019;2(10):1900075.
   Google Scholar
• Lawson KV, Kalisiak J, Lindsey EA, et al. Discovery of AB680: a Potent and Selective Inhibitor of CD73. J Med Chem. 2020;63(20):11448–11468.
   PubMed Web of Science ®Google Scholar
• Jeffrey JL, Lawson KV, Powers JP. Targeting metabolism of extracellular nucleotides via inhibition of ectonucleotidases CD73 and CD39. J Med Chem. 2020Nov25;63(22):13444–13465.
   PubMed Web of Science ®Google Scholar
• Du X, Moore J, Blank BR, et al. Orally Bioavailable Small-Molecule CD73 Inhibitor (OP-5244) reverses immunosuppression through blockade of adenosine production. J Med Chem. 2020;63(18):10433–10459.
   PubMed Web of Science ®Google Scholar
• Schmies CC, Rolshoven G, Idris RM, et al. Fluorescent Probes for Ecto-5′-nucleotidase (CD73). ACS Med Chem Lett. 2020;11(11):2253–2260.
   PubMed Web of Science ®Google Scholar
• Schäkel L, Schmies CC, Idris RM, et al. Nucleotide Analog ARL67156 as a Lead Structure for the Development of CD39 and Dual CD39/CD73 Ectonucleotidase Inhibitors. Front Pharmacol. 2020;11:1294.
   PubMed Web of Science ®Google Scholar
• Sharif EU, Kalisiak J, Lawson KV, et al. Discovery of potent and selective methylenephosphonic Acid CD73 Inhibitors. J Med Chem. 2021;64(1):845–860.
   PubMed Web of Science ®Google Scholar
• Ghoteimi R, Braka A, Rodriguez C, et al. 4-Substituted-1,2,3-triazolo nucleotide analogues as CD73 inhibitors, their synthesis, in vitro screening, kinetic and in silico studies. Bioorg Chem. 2021;107:104577.
   PubMed Web of Science ®Google Scholar
• Debien LPP, Kalisiak J, Lawson KV, et al. Inhibitors of adenosine 5ʹ-nucleotidase. WO2018/067424.
   Google Scholar
• Debien LPP, Jaen JC, Kalisiak J, et al. Modulators of 5ʹ-nucleotidase, ecto and the use thereof. WO2017/120508.
   Google Scholar
• Kalisiak J, Lawson KV, Leleti MR, et al. Inhibitors of CD73-mediated immunosuppression. WO2018/094148.
   Google Scholar
• Lu J, Gu J, Wu D, et al. CD73 inhibitors and pharmaceutical uses thereof. WO2020/051686.
   Google Scholar
• Jeffrey JL, Lawson KV, Miles DH Solid forms of a CD73 inhibitor and the use thereof. WO2020/123772
   Google Scholar
• Jacobson KA, Junker A, Dobelman C, et al. Purine and pyrimidine nucleotides as ecto-5ʹ-nucleotidase inhibitors. WO2020/037275.
   Google Scholar
• Müller CE, Brunschweiger A, Igbal J Ectonucleotidase inhibitors. WO2007/135195
   Google Scholar
• Du X, Eksterowicz J, Fantin VR, et al. CD73 inhibitors. WO2021/011689.
   Google Scholar
• Du X, Eksterowicz J, Fantin VR, et al. CD73 inhibitors. WO2019/213174.
   Google Scholar
• Du X, Eksterowicz J, Fantin VR, et al. CD73 inhibitors. WO2018/208980.
   Google Scholar
• Bailey S, Feng J, Kayser F, et al. CD73 inhibitors. WO2020/211668.
   Google Scholar
• Bailey S, Feng J, Kayser F, et al. CD73 inhibitors. WO2020/211672.
   Google Scholar
• Wang B, Yang H, Bedke K, et al. CD73 inhibitors and uses thereof. WO2018/183635.
   Google Scholar
• Wang B, Yang H, Bedke K, et al. compositions and methods for inhibiting CD73. WO2019/232319.
   Google Scholar
• Liu J, Wu H, Zhuang L, et al. CD73 inhibitors and pharmaceutical uses thereof. WO2020/047082.
   Google Scholar
• Deng H, Yu H, Chen Z CD73 inhibitor, preparation method therefor and application thereof. WO2020/221209.
   Google Scholar
• Deng H, Zhao B, Ying H, et al. Phosphonic acid derivative having CD73 inhibitory activity and preparation method and use thereof. WO2019/129059.
   Google Scholar
• Liu J, Zhuang L, Wu H, et al. Nucleoside and nucleotide analogues as CD73 inhibitors and therapeutic uses thereof. WO2018/208727.
   Google Scholar
• Dong P, Li X, Wang H, et al. Novel small molecule CD73 inhibitor, preparation and method therefor and pharmaceutical use thereof. WO2020/151707.
   Google Scholar
• Chen L, Billedeau RJ, Li J, et al. Ectonucleotidase inhibitors and methods of use thereof. WO2020/257429.
   Google Scholar
• Chen L, Li J, Sjogren E, et al. Ectonucleotidase inhibitors and methods of use thereof. WO2018/049145.
   Google Scholar
• Chen L, Billedeau RJ, Li J Ectonucleotidase inhibitors and methods of use thereof. WO2019/246403.
   Google Scholar
• Billedeau RJ, Li J, Chen L Ectonucleotidase inhibitors and methods of use thereof. WO2018/119284.
   Google Scholar
• Atanasov AG, Zotchev SB, Dirsch VM, et al. Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov. 2021;20(3):200–216.
   PubMed Web of Science ®Google Scholar
• Ripphausen P, Freundlieb M, Brunschweiger A, et al. Virtual Screening Identifies Novel Sulfonamide Inhibitors of ecto-5′-Nucleotidase. J Med Chem. 2012;55(14):6576–6581.
   PubMed Web of Science ®Google Scholar
• Varano F, Catarzi D, Vincenzi F, et al. Structural investigation on thiazolo[5,4-d]pyrimidines to obtain dual-acting blockers of CD73 and adenosine A2A receptor as potential antitumor agents. Bioorg Med Chem Lett. 2020;30(9):127067.
   PubMed Web of Science ®Google Scholar
• Beatty JW, Lindsey EA, Thomas-Tran R, et al. Discovery of potent and selective non-nucleotide small molecule Inhibitors of CD73. J Med Chem. 2020;63(8):3935–3955.
   PubMed Web of Science ®Google Scholar
• Beatty JW, Debien L, Drew SL, et al. CD73 inhibitors. WO2020/046813.
   Google Scholar
• Dally RD, Garcia Paredes MC, Heinz LJ, et al. CD73 inhibitors. WO2019/168744.
   Google Scholar
• Lyu S, Zhao Y, Zeng X, et al. Identification of phelligridin-based compounds as novel human CD73 Inhibitors. J Chem Inf Model. 2021;61(3):1275–1286.
   PubMed Web of Science ®Google Scholar
• Ashraf A, Shafiq Z, Khan Jadoon MS, et al. Synthesis, Characterization, and in silico studies of novel spirooxindole derivatives as Ecto-5ʹ-Nucleotidase Inhibitors. ACS Med Chem Lett. 2020;11(12):2397–2405.
   PubMed Web of Science ®Google Scholar
• Jin R, Liu L, Xing Y, et al. Dual mechanisms of novel CD73-Targeted Antibody and Antibody-Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function. Mol Cancer Ther. 2017 Sep;202(1). https://doi.org/10.1158/1535-7163. in press.
   Google Scholar
• Thompson EA, Powell JD. Inhibition of the adenosine pathway to potentiate cancer immunotherapy: potential for combinatorial approaches. Annu Rev Med. 2021;72(1):331–348.
   PubMedGoogle Scholar
• Perrot I, Paturel C, Gauthier L CD73 blockade. US Pat 2020/10,766,966.
   Google Scholar
• Caux C, Gauthier L, Gourdin N, et al. CD73 blockade. WO2017/064043.
   Google Scholar
• Liu Q, Zhou W, Yang H, et al. Binding molecule specific for CD73 and use of binding molecule. WO2020/244606.
   Google Scholar
• [cited 2021 mar 30]. Available from:https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/anti-cd73-monoclonal-antibody-medi9447.
   Google Scholar
• NCT03611556, see at https://clinicaltrials.gov/ct2/show/NCT03611556 ( last view on 2021 Mar 30
   Google Scholar
• Stefano JE, Lord DM, Zhou Y, et al. A highly potent CD73 biparatopic antibody blocks organization of the enzyme active site through dual mechanisms. J Biol Chem. 2020;295(52):18379–18389.
   PubMed Web of Science ®Google Scholar
• Tsukui H, Horie H, Koinuma K, et al. CD73 blockade enhances the local and abscopal effects of radiotherapy in a murine rectal cancer model. BMC Cancer. 2020;20(1):411.
   PubMed Web of Science ®Google Scholar
• Mishra CB, Tiwari M, Supuran CT. Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: where are we today? Med Res Rev. 2020;40(6):2485–2565.
   PubMed Web of Science ®Google Scholar
• Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov. 2008;7(2):168–181.
   PubMed Web of Science ®Google Scholar
• Supuran CT. Structure and function of carbonic anhydrases. Biochem J. 2016;473(14):2023–2032.
   PubMedGoogle Scholar
• Supuran CT, Winum JY. Introduction to zinc enzymes as drug targets. In: Supuran CT, Winum JY, editors. Drug design of zinc-enzyme inhibitors: functional, structural, and disease applications. Wiley, Hoboken; 2009. p. 3–12.
   Google Scholar
• Winum JY, Montero JL, Scozzafava A, et al. Zinc binding functions in the design of carbonic anhydrase inhibitors. In: Supuran CT, Winum JY, editors. Drug design of zinc-enzyme inhibitors: functional, structural, and disease applications. Wiley, Hoboken; 2009. p. 39–72.
   Google Scholar
• Supuran CT. How many carbonic anhydrase inhibition mechanisms exist? J Enzyme Inhib Med Chem. 2016;31(3):345–360.
   PubMed Web of Science ®Google Scholar
• Supuran CT. Carbon- versus sulphur-based zinc binding groups for carbonic anhydrase inhibitors? J Enzyme Inhib Med Chem. 2018;33(1):485–495.
   PubMed Web of Science ®Google Scholar
• Supuran CT. Exploring the multiple binding modes of inhibitors to carbonic anhydrases for novel drug discovery. Expert Opin Drug Discov. 2020;58(6):671–686.
   Google Scholar
• De Simone G, Supuran CT. (In)organic anions as carbonic anhydrase inhibitors. J Inorg Biochem. 2012;111:117–129.
   PubMed Web of Science ®Google Scholar
• De Clercq E. Tenofovir alafenamide (TAF) as the successor of tenofovir disoproxil fumarate (TDF). Biochem Pharmacol. 2016;119:1–7.
   PubMed Web of Science ®Google Scholar
• Viviani LG, Piccirillo E, Ulrich H, et al. Virtual screening approach for the identification of hydroxamic acids as novel human Ecto-5′-Nucleotidase Inhibitors. J Chem Inf Model. 2020;2(2):621–630.
   Google Scholar
• Jonsson BH, Liljas A. Comments to the editor due to the response by the supuran group to our article. Biophys J. 2021;120(1):182–183.
   PubMed Web of Science ®Google Scholar
• Giatromanolaki A, Kouroupi M, Pouliliou S, et al. Ectonucleotidase CD73 and CD39 expression in non-small cell lung cancer relates to hypoxia and immunosuppressive pathways. Life Sci. 2020;259:118389.
   PubMed Web of Science ®Google Scholar
• Petruk N, Tuominen S, Åkerfelt M, et al. CD73 facilitates EMT progression and promotes lung metastases in triple-negative breast cancer. Sci Rep. 2021;11(1):6035.
   PubMed Web of Science ®Google Scholar
• Nguyen AM, Zhou J, Sicairos B, et al. Upregulation of CD73 confers acquired radioresistance and is required for maintaining irradiation-selected pancreatic cancer cells in a mesenchymal state. Mol Cell Proteomics. 2020 Feb;19(2):375–389.
   PubMed Web of Science ®Google Scholar
• Azambuja JH, Schuh RS, Michels LR, et al. Blockade of CD73 delays glioblastoma growth by modulating the immune environment. Cancer Immunol Immunother. 2020 Sep;83(4):1801–1812.
   Google Scholar
• Tripathi A, Lin E, Xie W, et al. Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma. J Immunother Cancer. 2020;8(2):e001467.
   PubMed Web of Science ®Google Scholar
• Turiello R, Capone M, Giannarelli D, et al. Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy. J Immunother Cancer. 2020 Dec;8(2):e001689.
   PubMed Web of Science ®Google Scholar
• Neri D, Supuran CT. Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov. 2011 Sep 16;10(10):767–777.
   PubMed Web of Science ®Google Scholar
• McDonald PC, Chia S, Bedard PL, et al. A Phase 1 Study of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors. Am J Clin Oncol. 2020;43(7):484–490.
   PubMed Web of Science ®Google Scholar
• Angeli A, Carta F, Nocentini A, et al. Carbonic anhydrase inhibitors targeting metabolism and tumor microenvironment. Metabolites. 2020;10(10):412.
   PubMed Web of Science ®Google Scholar
• Supuran CT. Experimental carbonic anhydrase inhibitors for the treatment of hypoxic tumors. J Exp Pharmacol. 2020;12:603–617.
   PubMedGoogle Scholar