1. Introduction
2. Inhibitors of the PD-1/PD-L1 Interaction
2.1. Peptides and Peptidomimetics as Inhibitors of the PD-1/PD-L1 Pathway
2.2. Nonpeptidic Small-Molecule Inhibitors
3. Conclusions
Supplementary Materials
Funding
Conflicts of Interest
References
- Agata, Y.; Kawasaki, A.; Nishimura, H.; Ishida, Y.; Tsubat, T.; Yagita, H.; Honjo, T. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 1996, 8, 765–772. [Google Scholar] [CrossRef]
- Nishimura, H.; Agata, Y.; Kawasaki, A.; Sato, M.; Imamura, S.; Minato, N.; Yagita, H.; Nakano, T.; Honjo, T. Developmentally regulated expression of the PD-1 protein on the surface of double-negative(CD4(−)CD8(−)) thymocytes. Int. Immunol. 1996, 8, 773–780. [Google Scholar] [CrossRef]
- Simon, S.; Labarriere, N. PD-1 expression on tumor-specific T cells: Friend or foe for immunotherapy? Oncoimmunology 2018, 7, e1364828. [Google Scholar] [CrossRef]
- Zak, K.M.; Grudnik, P.; Magiera, K.; Dömling, A.; Dubin, G.; Holak, T.A. Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2. Structure 2017, 25, 1163–1174. [Google Scholar] [CrossRef]
- Lee, H.T.; Lee, S.H.; Heo, Y.-S. Molecular Interactions of Antibody Drugs Targeting PD-1, PD-L1, and CTLA-4 in Immuno-Oncology. Molecules 2019, 24, 1190. [Google Scholar] [CrossRef]
- Ishida, Y.; Agata, Y.; Shibahara, K.; Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992, 11, 3887–3895. [Google Scholar] [CrossRef]
- Shinohara, T.; Taniwaki, M.; Ishida, Y.; Kawaichi, M.; Honjo, T. Structure and Chromosomal Localization of the Human PD-1 Gene (PDCD1). Genomics 1994, 23, 704–706. [Google Scholar] [CrossRef]
- Francisco, L.M.; Sage, P.T.; Sharpe, A.H. The PD-1 pathway in tolerance and autoimmunity. Immunol. Rev. 2010, 236, 219–242. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.; Schwartz, J.-C.D.; Guo, X.; Bhatia, S.; Cao, E.; Chen, L.; Zhang, Z.-Y.; Edidin, M.A.; Nathenson, S.G.; Almo, S.C. Structural and Functional Analysis of the Costimulatory Receptor Programmed Death-1. Immunity 2004, 20, 337–347. [Google Scholar] [CrossRef]
- Flies, D.B.; Sandler, B.J.; Sznol, M.; Chen, L. Blockade of the B7-H1/PD-1 pathway for cancer immunotherapy. Yale J. Biol. Med. 2011, 84, 409–421. [Google Scholar]
- Zhan, M.M.; Hu, X.Q.; Liu, X.X.; Ruan, B.F.; Xu, J.; Liao, C. From monoclonal antibodies to small molecules: The development of inhibitors targeting the PD-1/PD-L1 pathway. Drug Discov. Today 2016, 21, 1027–1036. [Google Scholar] [CrossRef]
- Ghiotto, M.; Gauthier, L.; Serriari, N.; Pastor, S.; Truneh, A.; Nunès, J.A.; Olive, D. PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1. Int. Immunol. 2010, 22, 651–660. [Google Scholar] [CrossRef]
- Carter, L.L.; Fouser, L.A.; Jussif, J.; Fitz, L.; Deng, B.; Wood, C.R.; Collins, M.; Honjo, T.; Freeman, G.J.; Carreno, B.M. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2. Eur. J. Immunol. 2002, 32, 634–643. [Google Scholar] [CrossRef]
- Hamanishi, J.; Mandai, M.; Iwasaki, M.; Okazaki, T.; Tanaka, Y.; Yamaguchi, K.; Higuchi, T.; Yagi, H.; Takakura, K.; Minato, N.; et al. Programmed cell death 1 ligand 1 and tumor- infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl. Acad. Sci. USA 2007, 104, 3360–3365. [Google Scholar] [CrossRef]
- Tumeh, P.C.; Harview, C.L.; Yearley, J.H.; Shintaku, I.P.; Taylor, E.J.; Robert, L.; Chmielowski, B.; Spasic, M.; Henry, G.; Ciobanu, V. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014, 515, 568–571. [Google Scholar] [CrossRef]
- Parsa, A.T.; Waldron, J.S.; Panner, A.; Crane, C.A.; Parney, I.F.; Barry, J.J.; Cachola, K.E.; Murray, J.C.; Tihan, T.; Jensen, M.C.; et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat. Med. 2007, 13, 84–88. [Google Scholar] [CrossRef]
- Marzec, M.; Zhang, Q.; Goradia, A.; Raghunath, P.N.; Liu, X.B.; Paessler, M.; Wang, H.Y.; Wysocka, M.; Cheng, M.G.; Ruggeri, B.A.; et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274(PD-L1, B7- H1). Proc. Natl. Acad. Sci. USA 2008, 105, 20852–20857. [Google Scholar] [CrossRef] [PubMed]
- Lee, S.K.; Seo, S.H.; Kim, B.S.; Kim, C.D.; Lee, J.H.; Kang, J.S.; Maeng, P.J.; Lim, J.S. IFN-gamma regulates the expression of B7-H1 in dermal fibroblast cells. J. Dermatol. Sci. 2005, 40, 95–103. [Google Scholar] [CrossRef]
- Kelly, P.N. The Cancer Immunotherapy Revolution. Science 2018, 359, 1344–1345. [Google Scholar] [CrossRef]
- Ribas, A.; Wolchok, J.D. Cancer immunotherapy using checkpoint blockade. Science 2018, 359, 1350–1355. [Google Scholar] [CrossRef]
- Nisbet, I. Cancer immunotherapy comes of age (Finally!). Australas. Biotechnol. 2016, 26, 38–40. [Google Scholar]
- Ledford, H.; Else, H.; Warren, M. Cancer immunologists scoop medicine Nobel prize. Nature 2018, 562, 20–21. [Google Scholar] [CrossRef]
- Garon, E.B.; Rizvi, N.A.; Hui, R.; Leighl, N.; Balmanoukian, A.S.; Eder, J.P.; Patnaik, A.; Aggarwal, C.; Gubens, M.; Horn, L.; et al. Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2015, 372, 2018–2202. [Google Scholar] [CrossRef]
- Hoos, A. Development of immuno-oncology drugs—From CTLA4 to PD1 to the next generations. Nat. Rev. Drug Discov. 2016, 15, 235–247. [Google Scholar] [CrossRef]
- Topalian, S.L.; Drake, C.G.; Pardoll, D.M. Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell 2015, 27, 450–461. [Google Scholar] [CrossRef]
- Tan, S.; Zhang, C.W.-H.; Gao, G.F. Seeing is believing: Anti-PD-1/PD-L1 monoclonal antibodies in action for checkpoint blockade tumor immunotherapy. Signal Transduct. Target. Ther. 2016, 1, 16029. [Google Scholar] [CrossRef]
- Zak, K.M.; Kitel, R.; Przetocka, S.; Golik, P.; Guzik, K.; Musielak, B.; Domling, A.; Dubin, G.; Holak, T.A. Structure of the complex of human programmed death 1, PD-1, and Its ligand PD-L1. Structure 2015, 23, 2341–2348. [Google Scholar] [CrossRef]
- Weinmann, H. Cancer Immunotherapy: Selected Targets and Small-Molecule Modulators. ChemMedChem 2016, 11, 450–466. [Google Scholar] [CrossRef]
- Zarganes-Tzitzikas, T.; Konstantinidou, M.; Gao, Y.; Krzemien, D.; Zak, K.; Dubin, G.; Holak, T.A.; Krzemien, D.; Zak, K.; Dubin, G.; et al. Inhibitors of programmed cell death 1 (PD-1): A patent review (2010–2015). Expert Opin. Ther. Pat. 2016, 3776, 1–6. [Google Scholar] [CrossRef]
- Toogood, P.L. Small molecule immuno-oncology therapeutic agents. Bioorg. Med. Chem. Lett. 2018, 28, 319–329. [Google Scholar] [CrossRef]
- Lee, J.Y.; Lee, H.T.; Shin, W.; Chae, J.; Choi, J.; Kim, S.H.; Lim, H.; Won Heo, T.; Park, K.Y.; Lee, Y.J.; et al. Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy. Nat. Commun. 2016, 7, 13354. [Google Scholar] [CrossRef]
- Konstantinidou, M.; Zarganes-Tzitzikas, T.; Magiera-Mularz, K.; Holak, T.A.; Dömling, A. Immune Checkpoint PD-1/PD-L1: Is There Life Beyond Antibodies? Angew. Chem. Int. Ed. 2018, 57, 4840–4848. [Google Scholar] [CrossRef]
- Wang, T.; Wu, X.; Guo, C.; Zhang, K.; Xu, J.; Li, Z.; Jiang, S. Development of Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Signaling Pathway. J. Med. Chem. 2019, 62, 1715–1730. [Google Scholar] [CrossRef] [PubMed]
- Chen, T.; Li, Q.; Liu, Z.; Chen, Y.; Feng, F.; Sun, H. Peptide-based and small synthetic molecule inhibitors on PD-1/PD-L1 pathway: A new choice for immunotherapy? Eur. J. Med. Chem. 2019, 161, 378–398. [Google Scholar] [CrossRef]
- Sasikumar, P.G.N.; Ramachandra, M.; Vadlamani, S.K.; Vemula, K.R.; Satyam, L.K.; Subbarao, K.; Shrimali, K.R.; Kandepudu, S. Immunosuppression Modulating Compounds. US20110318373A1, 29 December 2011. [Google Scholar]
- Sasikumar, P.G.; Satyam, L.K.; Shrimali, R.K.; Subbarao, K.; Ramachandra, R.; Vadlamani, S.; Reddy, A.; Kumar, A.; Srinivas, A.; Reddy, S.; et al. Abstract 2850: Demonstration of anti-tumor efficacy in multiple preclinical cancer models using a novel peptide inhibitor (Aurigene-012) of the PD1 signaling pathway. Cancer Res. 2012, 72. [Google Scholar] [CrossRef]
- Sasikumar, P.G.N.; Ramachandra, M.; Vadlamani, S.K.; Shrimali, K.; Subbarao, K. Therapeutic Compounds for Immunomodulation. WO2012168944, 13 December 2012. [Google Scholar]
- Miller, M.M.; Mapelli, C.; Allen, M.P.; Bowsher, M.S.; Boy, K.M.; Gillis, E.P.; Langley, D.R.; Mull, E.; Poirier, M.A.; Sanghvi, N.; et al. Macrocyclic Inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD- L1 Protein/Protein Interactions. WO2014151634, 25 September 2014. [Google Scholar]
- Miller, M.M.; Mapelli, C.; Allen, M.P.; Bowsher, M.S.; Gillis, E.P.; Langley, D.R.; Mull, E.; Poirier, M.A.; Sanghvi, N.; Sun, L.Q.; et al. Macrocyclic Inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD-LI Protein/Protein Interactions. WO2016039749, 17 March 2016. [Google Scholar]
- Magiera-Mularz, K.; Skalniak, L.; Zak, K.M.; Musielak, B.; Rudzinska-Szostak, E.; Berlicki, Ł.; Kocik, J.; Grudnik, P.; Sala, D.; Zarganes-Tzitzikas, T.; et al. Bioactive Macrocyclic Inhibitors of the PD-1/PD-L1 Immune Checkpoint. Angew. Chem. Int. Ed. Engl. 2017, 56, 13732–13735. [Google Scholar] [CrossRef]
- Zak, K.M.; Grudnik, P.; Guzik, K.; Zieba, B.J.; Musielak, B.; Dömling, A.; Dubin, G.; Holak, T.A. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). Oncotarget 2016, 7, 30323–30335. [Google Scholar] [CrossRef]
- Guzik, K.; Zak, K.M.; Grudnik, P.; Magiera, K.; Musielak, B.; Törner, R.; Skalniak, L.; Dömling, A.; Dubin, G.; Holak, T.A. Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1. J. Med. Chem. 2017, 60, 5857–5867. [Google Scholar] [CrossRef]
- Skalniak, L.; Zak, K.M.; Guzik, K.; Magiera, K.; Musielak, B.; Pachota, M.; Szelazek, B.; Kocik, J.; Grudnik, P.; Tomala, M.; Krzanik, S.; et al. Small-molecule inhibitors of PD-1/PD-L1 immune checkpoint alleviate the PD-L1-induced exhaustion of T-cells. Oncotarget 2017, 8, 72167–72181. [Google Scholar] [CrossRef]
- Perry, E.; Mills, J.J.; Zhao, B.; Wang, F.; Sun, Q.; Christov, P.P.; Tarr, J.C.; Rietz, T.A.; Olejniczak, E.T.; Lee, T.; et al. Fragment-based screening of programmed death ligand 1 (PD-L1). Bioorg. Med. Chem. Lett. 2019, 29, 786–790. [Google Scholar] [CrossRef] [PubMed]
- Patil, S.P.; Yoon, S.-C.; Aradhya, A.G.; Hofer, J.; Fink, M.A.; Enley, E.S.; Fisher, J.E.; Herb, M.C.; Klingos, A.; Proulx, J.T.; et al. Macrocyclic Compounds from Ansamycin Antibiotic Class as Inhibitors of PD1–PDL1 Protein–Protein Interaction. Chem. Pharm. Bull. 2018, 66, 773–778. [Google Scholar] [CrossRef] [PubMed]
- Sasikumar, P.G.N.; Ramachandra, M.; Naremaddepalli, S.S.S. Peptidomimetic Compounds as Immunomdulators. US20130237580, 12 September 2013. [Google Scholar]
- Sasikumar, P.G.N.; Ramachandra, M.; Naremaddepalli, S.S.S. Immunomodulating Peptidomimetic Derivatives. WO2015036927A1, 19 March 2015. [Google Scholar]
- Sasikumar, P.G.N.; Ramachandra, M.; Naremaddepalli, S.S.S. Therapeutic Immunomodulating Compounds. WO2015044900A1, 2 April 2015. [Google Scholar]
- Sasikumar, P.G.N.; Ramachandra, M.; Naremaddepalli, S.S.S.; Prasad, A. 3-Substituted-1,2,4-Oxadiazole and Thiadiazole Compounds as Immunomodulators. US20180044329A1, 15 February 2018. [Google Scholar]
- Böger, C.; Behrens, H.M.; Krüger, S.; Röcken, C. The novel negative checkpoint regulator VISTA is expressed in gastric carcinoma and associated with PD-L1/PD-1: A future perspective for a combined gastric cancer therapy? OncoImmunology 2017, 6, e1293215. [Google Scholar] [CrossRef]
- Sasikumar, P.G.N.; Ramachandra, M.; Naremaddepalli, S.S.S. Dual Inhibitors of VISTA and PD-1 Pathways. WO2018073754, 26 April 2018. [Google Scholar]
- Sasikumar, P.G.N.; Ramachandra, M.; Naremaddepalli, S.S.S. 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives as Immunomodulators. WO2015033301A1, 12 March 2015. [Google Scholar]
- Sasikumar, P.G.N.; Ramachandra, M.; Naremaddepalli, S.S.S. Cyclic Substituted-1,3,4-Oxadiazole and Thiadiazole Compounds as Immunomodulators. WO2018051255A1, 22 March 2018. [Google Scholar]
- Sasikumar, P.G.N.; Ramachandra, M.; Naremaddepalli, S.S.S. 1,2,4-Oxadiazole and Thiadiazole Compounds as Immunomodulators. WO2016142833, 15 September 2016. [Google Scholar]
- Sasikumar, P.G.N.; Ramachandra, M.; Naremaddepalli, S.S.S.; Prasad, A. 3-Substituted 1,3,4-Oxadiazole and Thiadiazole Compounds as Immunomodulators. WO2016142894A1, 15 September 2016. [Google Scholar]
- Sasikumar, P.G.N.; Ramachandra, M.; Naremaddepalli, S.S.S. 1,2,4-Oxadiazole Derivatives as Immunomodulators. US10173989B2, 8 January 2019. [Google Scholar]
- Sasikumar, P.G.N.; Ramachandra, M.; Naremaddepalli, S.S.S. 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives as Immunomodulators. US10160736B2, 25 December 2018. [Google Scholar]
- Shaabani, S.; Huizinga, H.P.S.; Butera, R.; Kouchi, A.; Guzik, K.; Magiera-Mularz, K.; Holak, T.A.; Dömling, A. A patent review on PD-1/PD-L1 antagonists: Small molecules, peptides, and macrocycles (2015–2018). Expert Opin. Ther. Pat. 2018, 28, 665–678. [Google Scholar] [CrossRef] [PubMed]
- Sharpe, A.H.; Butte, M.J.; Oyama, S. Modulators of Immunoinhibitory Receptor PD-1, and Methods of Use Thereof. WO2011082400 A2, 7 July 2011. [Google Scholar]
- Chupak, L.S.; Zheng, X. Compounds useful as immunomodulators. WO2015034820 A1, 12 March 2015. [Google Scholar]
- Chupak, L.S.; Ding, M.; Martin, S.W.; Zheng, X.; Hewawasam, P.; Connolly, T.P.; Xu, N.; Yeung, K.-S.; Zhu, J.; Langley, D.R.; et al. Compounds Useful as Immunomodulators. WO2015160641, 22 October 2015. [Google Scholar]
- Yeung, K.S.; Connolly, T.P.; Frennesson, D.B.; Grant-Young, K.A.; Hewawasam, P.; Langley, D.R.; Meng, Z.; Mull, E.; Parcella, K.E.; Saulnier, M.G.; et al. Compounds Useful as Immunomodulators. WO2017/066227, 20 April 2017. [Google Scholar]
- Yeung, K.S.; Grant-Young, K.A.; Zhu, J.; Saulnier, M.G.; Frennesson, D.B.; Meng, Z.; Scola, P.M. 1,3-dihydroxy-phenyl derivatives useful as immunomodulators. WO2018/009505 A1, 11 January 2018. [Google Scholar]
- Yeung, K.S.; Grant-Young, K.A.; Zhu, J.; Saulnier, M.G.; Frennesson, D.B.; Langley, D.R.; Hewawasam, P.; Wang, A.X.; Zhang, Z.; Meng, Z.; et al. Biaryl Compounds Useful as Immunomodulators. WO2018/044963A1, 8 March 2018. [Google Scholar]
- Yeung, K.S.; St. Laurent, D.R.; Romine, J.L.; Scola, P.M. Substituted Isoquionline Derivatives as Immunomodulators. WO2018/183171 A1, 18 October 2018. [Google Scholar]
- Krajewski, M.; Rothweiler, U.; D’Silva, L.; Majumdar, S.; Klein, C.; Holak, T.A. An NMR-based antagonist induced dissociation assay for targeting the ligand-protein and protein-protein interactions in competition binding experiments. J. Med. Chem. 2007, 50, 4382–4387. [Google Scholar] [CrossRef] [PubMed]
- D-Silva, L.D.; Ozdowy, P.; Krajewski, M.; Rothweiler, U.; Singh, M.; Holak, T.A. Monitoring the Effects of Antagonists on Protein—Protein Interactions with NMR Spectroscopy. J. Am. Chem. Soc. 2005, 127, 13220–13226. [Google Scholar] [CrossRef] [PubMed]
- Krajewski, M.; Ozdowy, P.; D’Silva, L.; Rothweiler, U.; Holak, T.A. NMR indicates that the small molecule RITA does not block p53-MDM2 binding in vitro. Nat. Med. 2005, 11, 1135–1136. [Google Scholar] [CrossRef]
- Wu, L.; Shen, B.; Li, J.; Li, Z.; Liu, K.; Zhang, F.; Yao, W. Heterocyclic Compounds as Immunomodulators. US20170107216 A1, 20 April 2017. [Google Scholar]
- Li, J.; Wu, L.; Yao, W. Heterocyclic Compounds as Immunomodulators. WO2017087777 A1, 26 May 2017. [Google Scholar]
- Li, Z.; Wu, L.; Yao, W. Heterocyclic Compounds as Immunomodulators. WO2017192961 A1, 9 November 2017. [Google Scholar]
- Lu, L.; Qian, D.Q.; Wu, L.; Yao, W. Heterocyclic Compounds as Immunomodulators. WO2017205464 A1, 30 November 2017. [Google Scholar]
- Lajkiewicz, N.; Wu, L.; Yao, W. Heterocyclic compounds as immunomodulators. US 20170174679 A1, 22 June 2017. [Google Scholar]
- Wu, L.; Yu, Z.; Zhang, F.; Yao, W. N-Phenyl-Pyridine-2-Carboxamide Derivatives and Their Use as PD-1/PD-L1 Protein/Protein Interaction Modulators. WO2017106634 A1, 22 June 2017. [Google Scholar]
- Yu, Z.; Wu, L.; Yao, W. Heterocyclic Compounds as Immunomodulators. WO2018013789 A1, 18 January 2018. [Google Scholar]
- Wu, L.; Zhang, F.; Yao, W. Heterocyclic Compounds as Immunomodulators. WO2018044783 A1, 8 March 2018. [Google Scholar]
- Xiao, K.; Zhang, F.; Wu, L.; Yao, W. Heterocyclic compounds as immunomodulators. US20170362253 A1, 21 December 2017. [Google Scholar]
- Wu, L.; Qian, D.Q.; Lu, L.; Lajkiewicz, N.; Konkol, L.C.; Li, Z.; Zhang, F.; Li, J.; Wang, H.; Xu, M.; et al. Heterocyclic Compounds as Immunomodulators. US 20180177784 A1, 28 June 2018. [Google Scholar]
- Lange, C.; McMurtrie, D.J.; Malathong, V.; Punna, S.; Singh, R.; Yang, J.; Zhang, P. Immunomodulator Compounds. WO2018005374A1, 11 January 2018. [Google Scholar]
- Lange, C.; McMurtrie, D.J.; Malathong, V.; Mali, V.R.; Mcmahon, J.; Roth, H.S.; Singh, R.; Wang, Y.; Yang, J.; Zhang, P. Immunomodulator Compounds. WO2019023575A1, 31 January 2019. [Google Scholar]
- Vilalta Colomer, M.; Li, S.; Malathong, V.; Lange, C.; McMurtrie, D.; Yang, J.; Roth, H.; McMahon, J.; Campbell, J.J.; Ertl, L.S.; et al. A small molecule human PD-1/PD-L1 inhibitor promotes T cell immune activation and reduces tumor growth in a preclinical model. Ann. Oncol. 2018, 29. [Google Scholar] [CrossRef]
- Feng, Z.; Chen, X.; Yang, Y.; Zhou, C.; Lai, F.; Ji, M.; Jing, X.; Xue, N.; Zheng, Y.; Chen, H.; et al. Phenylate Derivative, Preparation Method Therefor, and Pharmaceutical Composition and Uses Therof. WO2017202276 A1, 30 November 2017. [Google Scholar]
- Li, S.; Xiao, J.; Liu, A.; Wei, X.; Zhong, W.; Zheng, Z.; Wang, X.; Xie, Y.; Zhao, G.; Li, H. Resorcinol Compound and Medicinal Use Thereof. CN107286057 A, 24 October 2017. [Google Scholar]
- Sun, H.; Xin, T.; Wen, X.; Wu, Y.; Yuan, H. 2-Substituted Isonicotinic Acid Compound, Preparation Method and Application Thereof. CN106632021, 10 May 2017. [Google Scholar]
- Wang, M. Symmetric or Semi-symmetric Compounds Useful as Immunomodulators. WO2018/026971, 8 February 2019. [Google Scholar]
- Webber, S.; Almassy, R.J. Immune Checkpoint Inhibitors Compositions and Methods Thereof. WO2018/045142 A1, 8 March 2018. [Google Scholar]
- Aktoudianakis, E.; Appleby, T.; Aesop, C.; Zhimin, D.; Graupe, M.; Guerrero, J.; Jabri, S.; Lad, L.; Machicao Tello, P.A.; Medley, J.W.; et al. PD-1/PD-L1 INHIBITORS. US 2018/0305315 A1, 25 October 2018. [Google Scholar]
- Qin, M.; Cao, Q.; Zheng, S.; Tian, Y.; Zhang, H.; Xie, J.; Xie, H.; Liu, Y.; Zhao, Y.; Gong, P. Discovery of [1,2,4]Triazolo[4,3-a]pyridines as Potent Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction. J. Med. Chem. 2019, 62, 4703–4715. [Google Scholar] [CrossRef]
- Patil, S.P.; Fink, M.A.; Enley, E.S.; Fisher, J.E.; Herb, M.C.; Klingos, A.; Proulx, J.T.; Fedorky, M.T. Identification of Small-Molecule Inhibitors of PD-1/PD-L1 Protein-Protein Interaction. ChemistrySelect 2018, 3, 2185–2189. [Google Scholar] [CrossRef]
- Monga, M.; Sausville, E.A. Developmental therapeutics program at the NCI: Molecular target and drug discovery process. Leukemia 2002, 16, 520–526. [Google Scholar] [CrossRef]
- Dömling, A. Inhibitors of the PD-1/PD-L1 protein/protein interaction. WO2017/118762 A1, 13 July 2017. [Google Scholar]
- Dömling, A. 3-Cyanotiphene Derivatives as Inhibitors of the PD-1/PD-L1 Interaction. WO2019/008152 A1, 10 January 2019. [Google Scholar]
- Dömling, A. 3-(azolylmethoxy)biphenyl Derivatives as Inhibitors of the PD-1/PD-L1 Protein-Protein Interaction. WO2019/008154 A1, 10 January 2019. [Google Scholar]
- Dömling, A. Inhibitors of the PD-1/PD-L1 interaction. WO2019/008156 A1, 10 January 2019. [Google Scholar]
- Wang, Y.; Xu, Z.; Wu, T.; He, M.; Zhang, N. 2018, Aromatic Acetylene or Aromatic Ethylene Compound, Intermediate, Preparation Method, Pharmaceutical Composition and Use Thereof. WO2018006795, 11 January 2018. [Google Scholar]
- Wang, Y.; Zhou, H.; Zhang, N.; Wang, F.; Zhao, Q.; Wu, T.; Zhu, H.; Liu, Y. Abstract 3851: Novel small-molecule inhibitor of PD1/PDL1 pathway demonstrated single agent and drug combo effectiveness in cancer immunotherapy. In Proceedings of the American Association for Cancer Research Annual Meeting, Chicago, IL, USA, 14–18 April 2018; AACR Cancer Research: Philadelphia, PA, USA, 2018; Volume 78. [Google Scholar]



































© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).