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ISSN (Online): 1875-5607

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Mini-Review Article

Cancer Immunotherapy: An Overview of Small Molecules as Inhibitors of the Immune Checkpoint PD-1/PD-L1 (2015-2021)

Author(s): Emma Baglini, Silvia Salerno, Elisabetta Barresi, Tiziano Marzo, Federico Da Settimo and Sabrina Taliani*

Volume 22, Issue 14, 2022

Published on: 18 April, 2022

Page: [1816 - 1827] Pages: 12

DOI: 10.2174/1389557522666220217110925

Price: $65

Abstract

In 2018, James Allison and Tasuku Honjo received the Nobel Prize in physiology or medicine to discover tumor therapy by inhibition of negative immune regulation. Immunotherapy stimulates T-cells to fight cancer cells by blocking different immune checkpoint pathways. The interaction between programmed cell death 1 (PD-1) and its ligand PD-L1 (Programmed cell death ligand 1) is one of the main pathways. Of note, interfering with this pathway is already exploited in clinical cancer therapy, demonstrating that it is one of the key factors involved in the immune escape mechanism of cancer. The development of monoclonal antibodies (mAbs) that possess the ability to inhibit the interactions between PD-1/PD-L1 has radically made the difference in cancer immunotherapy. Yet, due to the many drawbacks of this therapy, the research shifted its efforts towards the development of novel small molecules. This may constitute hope and an arduous challenge in fighting cancer. This paper reviews the recent primary literature concerning the development of novel small molecules able to block the interaction between PD-1 and its ligand PD-L1.

Keywords: Immunotherapy, programmed cell death protein 1, programmed cell death ligand 1, immune checkpoint, cancer, small molecules.

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[1]
Rius, M.; Lyko, F. Epigenetic cancer therapy: Rationales, targets and drugs. Oncogene, 2012, 31(39), 4257-4265.
[http://dx.doi.org/10.1038/onc.2011.601] [PMID: 22179827]
[2]
Postow, M.A.; Callahan, M.K.; Wolchok, J.D. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol., 2015, 33(17), 1974-1982.
[http://dx.doi.org/10.1200/JCO.2014.59.4358] [PMID: 25605845]
[3]
Lee, L.; Gupta, M.; Sahasranaman, S. Immune Checkpoint inhibitors: An introduction to the next-generation cancer immunotherapy. J. Clin. Pharmacol., 2016, 56(2), 157-169.
[http://dx.doi.org/10.1002/jcph.591] [PMID: 26183909]
[4]
Hoos, A. Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations. Nat. Rev. Drug Discov., 2016, 15(4), 235-247.
[http://dx.doi.org/10.1038/nrd.2015.35] [PMID: 26965203]
[5]
Mellman, I.; Coukos, G.; Dranoff, G. Cancer immunotherapy comes of age. Nature, 2011, 480(7378), 480-489.
[http://dx.doi.org/10.1038/nature10673] [PMID: 22193102]
[6]
Ahmed, S.; Rai, K.R. Interferon in the treatment of hairy-cell leukemia. Best Pract. Res. Clin. Haematol., 2003, 16(1), 69-81.
[http://dx.doi.org/10.1016/S1521-6926(02)00084-1] [PMID: 12670466]
[7]
Rosenberg, S.A. IL-2: The first effective immunotherapy for human cancer. J. Immunol., 2014, 192(12), 5451-5458.
[http://dx.doi.org/10.4049/jimmunol.1490019] [PMID: 24907378]
[8]
Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer, 2012, 12(4), 252-264.
[http://dx.doi.org/10.1038/nrc3239] [PMID: 22437870]
[9]
Larsson, M.; Shankar, E.M.; Che, K.F.; Saeidi, A.; Ellegård, R.; Barathan, M.; Velu, V.; Kamarulzaman, A. Molecular signatures of T-cell inhibition in HIV-1 infection. Retrovirology, 2013, 10, 31-44.
[http://dx.doi.org/10.1186/1742-4690-10-31] [PMID: 23514593]
[10]
Freeman, G.J. Structures of PD-1 with its ligands: Sideways and dancing cheek to cheek. Proc. Natl. Acad. Sci. USA, 2008, 105(30), 10275-10276.
[http://dx.doi.org/10.1073/pnas.0805459105] [PMID: 18650389]
[11]
Chen, D.S.; Irving, B.A.; Hodi, F.S. Molecular pathways: Next-generation immunotherapy-inhibiting programmed death-ligand 1 and programmed death-1. Clin. Cancer Res., 2012, 18(24), 6580-6587.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-1362] [PMID: 23087408]
[12]
Iwai, Y.; Ishida, M.; Tanaka, Y.; Okazaki, T.; Honjo, T.; Minato, N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl. Acad. Sci. USA, 2002, 99(19), 12293-12297.
[http://dx.doi.org/10.1073/pnas.192461099] [PMID: 12218188]
[13]
O’Sullivan Coyne, G.; Madan, R.A.; Gulley, J.L. Nivolumab: Promising survival signal coupled with limited toxicity raises expectations. J. Clin. Oncol., 2014, 32(10), 986-988.
[http://dx.doi.org/10.1200/JCO.2013.54.5996] [PMID: 24590655]
[14]
Tartarone, A.; Roviello, G.; Lerose, R.; Roudi, R.; Aieta, M.; Zoppoli, P. Anti-PD-1 versus anti-PD-L1 therapy in patients with pretreated advanced non-small-cell lung cancer: A meta-analysis. Future Oncol., 2019, 15(20), 2423-2433.
[http://dx.doi.org/10.2217/fon-2018-0868] [PMID: 31237152]
[15]
Petrelli, F.; Ferrara, R.; Signorelli, D.; Ghidini, A.; Proto, C.; Roudi, R.; Sabet, M.N.; Facelli, S.; Garassino, M.C.; Luciani, A.; Roviello, G. Immune checkpoint inhibitors and chemotherapy in first-line NSCLC: A meta-analysis. Immunotherapy, 2021, 13(7), 621-631.
[http://dx.doi.org/10.2217/imt-2020-0224] [PMID: 33775103]
[16]
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.
[http://dx.doi.org/10.1038/sigtrans.2016.29] [PMID: 29263905]
[17]
Weber, J.S.; Hodi, S.F.; Wolchok, J.D.; Topalian, S.L.; Schadendorf, D.; Larkin, J.; Sznol, M.; Long, G.V.; Li, H.; Waxman, I.M.; Jiang, J.; Robert, C. Safety profile of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL): A pooled analysis. J. Clin. Oncol., 2015, 33, 785-792.
[http://dx.doi.org/10.1200/jco.2015.33.15_suppl.9018]
[18]
Robert, C.; Schachter, J.; Long, G.V.; Arance, A.; Grob, J.J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.; Lotem, M.; Larkin, J.; Lorigan, P.; Neyns, B.; Blank, C.U.; Hamid, O.; Mateus, C.; Shapira-Frommer, R.; Kosh, M.; Zhou, H.; Ibrahim, N.; Ebbinghaus, S.; Ribas, A. KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med., 2015, 372(26), 2521-2532.
[http://dx.doi.org/10.1056/NEJMoa1503093] [PMID: 25891173]
[19]
Muller, A.J.; Scherle, P.A. Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nat. Rev. Cancer, 2006, 6(8), 613-625.
[http://dx.doi.org/10.1038/nrc1929] [PMID: 16862192]
[20]
Adams, J.L.; Smothers, J.; Srinivasan, R.; Hoos, A. Big opportunities for small molecules in immuno-oncology. Nat. Rev. Drug Discov., 2015, 14(9), 603-622.
[http://dx.doi.org/10.1038/nrd4596] [PMID: 26228631]
[21]
Sun, X.; Roudi, R.; Dai, T.; Chen, S.; Fan, B.; Li, H.; Zhou, Y.; Zhou, M.; Zhu, B.; Yin, C.; Li, B.; Li, X. Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: A PRISMA systematic review and meta-analysis. BMC Cancer, 2019, 19(1), 558-570.
[http://dx.doi.org/10.1186/s12885-019-5701-6] [PMID: 31182061]
[22]
Bateman, A.C. Molecules in cancer immunotherapy: Benefits and side effects. J. Clin. Pathol., 2019, 72(1), 20-24.
[http://dx.doi.org/10.1136/jclinpath-2018-205370] [PMID: 30275101]
[23]
Chen, S.; Lee, L.F.; Fisher, T.S.; Jessen, B.; Elliott, M.; Evering, W.; Logronio, K.; Tu, G.H.; Tsaparikos, K.; Li, X.; Wang, H.; Ying, C.; Xiong, M.; VanArsdale, T.; Lin, J.C. Combination of 4-1BB agonist and PD-1 antagonist promotes antitumor effector/memory CD8 T cells in a poorly immunogenic tumor model. Cancer Immunol. Res., 2015, 3(2), 149-160.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0118] [PMID: 25387892]
[24]
Wu, Q.; Jiang, L.; Li, S.C.; He, Q.J.; Yang, B.; Cao, J. Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway. Acta Pharmacol. Sin., 2021, 42(1), 1-9.
[http://dx.doi.org/10.1038/s41401-020-0366-x] [PMID: 32152439]
[25]
Lee, A.; Duggan, S.; Deeks, E.D. Cemiplimab: A review in advanced cutaneous squamous cell carcinoma. Drugs, 2020, 80(8), 813-819.
[http://dx.doi.org/10.1007/s40265-020-01302-2] [PMID: 32306208]
[26]
Kwok, G.; Yau, T.C.; Chiu, J.W.; Tse, E.; Kwong, Y.L. Pembrolizumab (Keytruda). Hum. Vaccin. Immunother., 2016, 12(11), 2777-2789.
[http://dx.doi.org/10.1080/21645515.2016.1199310] [PMID: 27398650]
[27]
Shultz, D. Three drugs approved for urothelial carcinoma by FDA. Cancer Discov., 2017, 7(7), 659-660.
[http://dx.doi.org/10.1158/2159-8290.CD-NB2017-071] [PMID: 28546286]
[28]
Inman, B.A.; Longo, T.A.; Ramalingam, S.; Harrison, M.R. Atezolizumab: A PD-L1-blocking antibody for bladder cancer. Clin. Cancer Res., 2017, 23(8), 1886-1890.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1417] [PMID: 27903674]
[29]
Sidaway, P. Thyroid cancer: BRAF and/or TERT mutations increase mortality. Nat. Rev. Clin. Oncol., 2016, 13(11), 652.
[PMID: 27670230]
[30]
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(9), 665-678.
[http://dx.doi.org/10.1080/13543776.2018.1512706] [PMID: 30107136]
[31]
Musielak, B.; Kocik, J.; Skalniak, L.; Magiera-Mularz, K.; Sala, D.; Czub, M.; Stec, M.; Siedlar, M.; Holak, T.A.; Plewka, J. CA-170 - A potent small-molecule PD-L1 inhibitor or not? Molecules, 2019, 24(15), 2804-2816.
[http://dx.doi.org/10.3390/molecules24152804] [PMID: 31374878]
[32]
Sasikumar, P.G.N.; Ramachandra, M.; Naremaddepalli, S.S.S. 1,3,4-Oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators. WO Patent 2015033301 A1, 2015.
[33]
Clinical Trials.gov. A Study of CA-170 (Oral PD-L1, PD-L2 and VISTA Checkpoint Antagonist) in Patients With Advanced Tumors and Lymphomas. Available from: https://clinicaltrials.gov/ct2/show/NCT02812875?term=CA+170&cond=Tumor&draw=2&rank=1#studydesign
[34]
Chupak, L.S.; Zheng, X. Compounds useful as immunomodulators. WO Patent 2015034820 A1, 2015.
[35]
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(21), 30323-30335.
[http://dx.doi.org/10.18632/oncotarget.8730] [PMID: 27083005]
[36]
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(13), 5857-5867.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00293] [PMID: 28613862]
[37]
Basu, S.; Yang, J.; Xu, B.; Magiera-Mularz, K.; Skalniak, L.; Musielak, B.; Kholodovych, V.; Holak, T.A.; Hu, L. Design, synthesis, evaluation, and structural studies of C2-symmetric small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 protein-protein interaction. J. Med. Chem., 2019, 62(15), 7250-7263.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00795] [PMID: 31298541]
[38]
Cao, H.; Cheng, B.; Liu, T.; Chen, J. Synthesis and pharmacological evaluation of novel resorcinol biphenyl ether analogs as small molecule inhibitors of PD-1/PD-L1 with benign toxicity profiles for cancer treatment. Biochem. Pharmacol., 2021, 188, 114522.
[http://dx.doi.org/10.1016/j.bcp.2021.114522] [PMID: 33741334]
[39]
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(9), 4703-4715.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00312] [PMID: 30964291]
[40]
Qin, M.; Cao, Q.; Wu, X.; Liu, C.; Zheng, S.; Xie, H.; Tian, Y.; Xie, J.; Zhao, Y.; Hou, Y.; Zhang, X.; Xu, B.; Zhang, H.; Wang, X. Discovery of the programmed cell death-1/programmed cell death-ligand 1 interaction inhibitors bearing an indoline scaffold. Eur. J. Med. Chem., 2020, 186, 111856.
[http://dx.doi.org/10.1016/j.ejmech.2019.111856] [PMID: 31734021]
[41]
Zak, K.M.; Kitel, R.; Przetocka, S.; Golik, P.; Guzik, K.; Musielak, B.; Dömling, 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(12), 2341-2348.
[http://dx.doi.org/10.1016/j.str.2015.09.010] [PMID: 26602187]
[42]
Lin, D.Y.W.; Tanaka, Y.; Iwasaki, M.; Gittis, A.G.; Su, H.P.; Mikami, B.; Okazaki, T.; Honjo, T.; Minato, N.; Garboczi, D.N. The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc. Natl. Acad. Sci. USA, 2008, 105(8), 3011-3016.
[http://dx.doi.org/10.1073/pnas.0712278105] [PMID: 18287011]
[43]
Newman, D.J.; Cragg, G.M.; Snader, K.M. Natural products as sources of new drugs over the period 1981-2002. J. Nat. Prod., 2003, 66(7), 1022-1037.
[http://dx.doi.org/10.1021/np030096l] [PMID: 12880330]
[44]
Bailly, C.; Vergoten, G. Proposed mechanisms for the extracellular release of PD-L1 by the anticancer saponin platycodin D. Int. Immunopharmacol., 2020, 85, 106675.
[http://dx.doi.org/10.1016/j.intimp.2020.106675] [PMID: 32531711]

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