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Cancer Cell International
Published in: Cancer Cell International 1/2021

Open Access 01-12-2021 | Review

Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review

Authors: Chang Liu, Navindra P. Seeram, Hang Ma

Published in: Cancer Cell International | Issue 1/2021

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Abstract

Programmed death-1/programmed death ligand-1 (PD-1/PD-L1) based immunotherapy is a revolutionary cancer therapy with great clinical success. The majority of clinically used PD-1/PD-L1 inhibitors are monoclonal antibodies but their applications are limited due to their poor oral bioavailability and immune-related adverse effects (irAEs). In contrast, several small molecule inhibitors against PD-1/PD-L1 immune checkpoints show promising blockage effects on PD-1/PD-L1 interactions without irAEs. However, proper analytical methods and bioassays are required to effectively screen small molecule derived PD-1/PD-L1 inhibitors. Herein, we summarize the biophysical and biochemical assays currently employed for the measurements of binding capacities, molecular interactions, and blocking effects of small molecule inhibitors on PD-1/PD-L1. In addition, the discovery of natural products based PD-1/PD-L1 antagonists utilizing these screening assays are reviewed. Potential pitfalls for obtaining false leading compounds as PD-1/PD-L1 inhibitors by using certain binding bioassays are also discussed in this review.
Literature
1.
Fernandes M, Brabek J. Cancer, checkpoint inhibitors, and confusion. Lancet Oncol. 2017;18(11):e632.PubMedCrossRef
2.
Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991–8.PubMedCrossRef
3.
4.
5.
6.
7.
Liu J, Yuan Y, Chen W, Putra J, Suriawinata AA, Schenk AD, Miller HE, Guleria I, Barth RJ, Huang YH, et al. Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci USA. 2015;112(21):6682–7.PubMedCrossRefPubMedCentral
8.
Ramsay AG. Immune checkpoint blockade immunotherapy to activate anti-tumour T-cell immunity. Br J Haematol. 2013;162(3):313–25.PubMedCrossRef
9.
Bethune MT, Joglekar AV. Personalized T cell-mediated cancer immunotherapy: progress and challenges. Curr Opin Biotechnol. 2017;48:142–52.PubMedCrossRef
10.
Colombo MP, Piconese S. Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat Rev Cancer. 2007;7(11):880–7.PubMedCrossRef
11.
Kalos M, June CH. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity. 2013;39(1):49–60.PubMedCrossRef
12.
Paulos CM, June CH. Putting the brakes on BTLA in T cell-mediated cancer immunotherapy. J Clin Invest. 2010;120(1):76–80.PubMedCrossRef
13.
Wang M, Yin B, Wang HY, Wang RF. Current advances in T-cell-based cancer immunotherapy. Immunotherapy. 2014;6(12):1265–78.PubMedCrossRef
14.
15.
16.
Yan Y, Zhang L, Zuo Y, Qian H, Liu C. Immune checkpoint blockade in cancer immunotherapy: mechanisms, clinical outcomes, and safety profiles of PD-1/PD-L1 inhibitors. Arch Immunol Ther Exp. 2020;68(6):1–15.CrossRef
17.
Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, Iyer AK. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017;8:561.PubMedPubMedCentralCrossRef
18.
19.
20.
Saresella M, Rainone V, Al-Daghri NM, Clerici M, Trabattoni D. The PD-1/PD-L1 pathway in human pathology. Curr Mol Med. 2012;12(3):259–67.PubMedCrossRef
21.
Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443(7109):350–4.PubMedCrossRef
22.
Elrefaei M, Baker CA, Jones NG, Bangsberg DR, Cao H. Presence of suppressor HIV-specific CD8+ T cells is associated with increased PD-1 expression on effector CD8+ T cells. J Immunol. 2008;180(11):7757–63.PubMedCrossRef
23.
Wang LL, Li ZH, Hu XH, Muyayalo KP, Zhang YH, Liao AH. The roles of the PD-1/PD-L1 pathway at immunologically privileged sites. Am J Reprod Immunol. 2017;78(2):e12710.CrossRef
24.
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol. 2011;28(3):682–8.PubMedCrossRef
25.
Aguilar EJ, Ricciuti B, Gainor JF, Kehl KL, Kravets S, Dahlberg S, Nishino M, Sholl LM, Adeni A, Subegdjo S, et al. Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression. Ann Oncol. 2019;30(10):1653–9.PubMedCrossRef
26.
Ishizuka S, Sakata S, Yoshida C, Takaki A, Saeki S, Nakamura K, Fujii K. Successful treatment by pembrolizumab in a patient with end-stage renal disease with advanced non-small cell lung cancer and high PD-L1 expression. Respir Investig. 2018;56(4):361–4.PubMedCrossRef
27.
Fusi A, Festino L, Botti G, Masucci G, Melero I, Lorigan P, Ascierto PA. PD-L1 expression as a potential predictive biomarker. Lancet Oncol. 2015;16(13):1285–7.PubMedCrossRef
28.
Jiang C, Cao S, Li N, Jiang L, Sun T. PD-1 and PD-L1 correlated gene expression profiles and their association with clinical outcomes of breast cancer. Cancer Cell Int. 2019;19(1):1–9.CrossRef
29.
Gu X, Dong M, Liu Z, Mi Y, Yang J, Zhang Z, Liu K, Jiang L, Zhang Y, Dong S. Elevated PD-L1 expression predicts poor survival outcomes in patients with cervical cancer. Cancer Cell Int. 2019;19(1):1–9.CrossRef
30.
Shang J, Song Q, Yang Z, Sun X, Xue M, Chen W, Yang J, Wang S. Analysis of PD-1 related immune transcriptional profile in different cancer types. Cancer Cell Int. 2018;18(1):1–11.CrossRef
31.
32.
Salmaninejad A, Valilou SF, Shabgah AG, Aslani S, Alimardani M, Pasdar A, Sahebkar A. PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy. J Cell Physiol. 2019;234(10):16824–37.PubMedCrossRef
33.
Wu B, Sun X, Gupta HB, Yuan B, Li J, Ge F, Chiang HC, Zhang X, Zhang C, Zhang D, et al. Adipose PD-L1 modulates PD-1/PD-L1 checkpoint blockade immunotherapy efficacy in breast cancer. Oncoimmunology. 2018;7(11):e1500107.PubMedPubMedCentralCrossRef
34.
Tang F, Zheng P. Tumor cells versus host immune cells: whose PD-L1 contributes to PD-1/PD-L1 blockade mediated cancer immunotherapy? Cell Biosci. 2018;8:34.PubMedPubMedCentralCrossRef
35.
Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 2015;21(1):24–33.PubMedCrossRef
36.
Xin YuJ, Hodge JP, Oliva C, Neftelinov ST, Hubbard-Lucey VM, Tang J. Trends in clinical development for PD-1/PD-L1 inhibitors. Nat Rev Drug Discov. 2020;19(3):163–4.CrossRef
37.
38.
Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, Curiel TJ, Colon-Otero G, Hamid O, Sanborn RE, et al. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016;34(26):3119–25.PubMedPubMedCentralCrossRef
39.
Zinzani PL, Ribrag V, Moskowitz CH, Michot JM, Kuruvilla J, Balakumaran A, Zhang Y, Chlosta S, Shipp MA, Armand P. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017;130(3):267–70.PubMedPubMedCentralCrossRef
40.
Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, Kanai M, Mori Y, Matsumoto S, Chikuma S, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33(34):4015–22.PubMedCrossRef
41.
Reilly RM, Sandhu J, Alvarez-Diez TM, Gallinger S, Kirsh J, Stern H. Problems of delivery of monoclonal antibodies. Pharmaceutical and pharmacokinetic solutions. Clin Pharmacokinet. 1995;28(2):126–42.PubMedCrossRef
42.
Zhan MM, Hu XQ, Liu XX, Ruan BF, 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(6):1027–36.PubMedCrossRef
43.
Shaabani S, Huizinga HP, Butera R, Kouchi A, Guzik K, Magiera-Mularz K, Holak TA, 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):665–78.PubMedPubMedCentralCrossRef
44.
Ganesan A, Ahmed M, Okoye I, Arutyunova E, Babu D, Turnbull WL, Kundu JK, Shields J, Agopsowicz KC, Xu L, et al. Comprehensive in vitro characterization of PD-L1 small molecule inhibitors. Sci Rep. 2019;9(1):12392.PubMedPubMedCentralCrossRef
45.
46.
47.
Doronin A, Gordeev A, Kozlov A, Smirnova YA, Puchkova MY, Ekimova V, Basovskiy YI, Solovyev V. T-Cell engagers based bioassay for evaluation of PD-1/PD-L1 inhibitors activity. Biochem Mosc. 2019;84(7):711–9.CrossRef
48.
49.
Bally AP, Austin JW, Boss JM. Genetic and epigenetic regulation of PD-1 expression. J Immunol. 2016;196(6):2431–7.PubMedCrossRef
50.
51.
52.
53.
Cheng X, Veverka V, Radhakrishnan A, Waters LC, Muskett FW, Morgan SH, Huo J, Yu C, Evans EJ, Leslie AJ, et al. Structure and interactions of the human programmed cell death 1 receptor. J Biol Chem. 2013;288(17):11771–85.PubMedPubMedCentralCrossRef
54.
Brusa D, Serra S, Coscia M, Rossi D, D’Arena G, Laurenti L, Jaksic O, Fedele G, Inghirami G, Gaidano G. The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia. Haematologica. 2013;98(6):953–63.PubMedPubMedCentralCrossRef
55.
Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–8.PubMedCrossRef
56.
Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, Wu X, Ma J, Zhou M, Li X, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 2019;18(1):10.PubMedPubMedCentralCrossRef
57.
Escors D, Gato-Canas M, Zuazo M, Arasanz H, Garcia-Granda MJ, Vera R, Kochan G. The intracellular signalosome of PD-L1 in cancer cells. Signal Transduct Target Ther. 2018;3:26.PubMedPubMedCentralCrossRef
58.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.PubMedCrossRef
59.
Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, Bluestone JA. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signal. Nat Immunol. 2009;10(11):1185.PubMedPubMedCentralCrossRef
60.
Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574(1–3):37–41.PubMedCrossRef
61.
Arasanz H, Gato-Canas M, Zuazo M, Ibanez-Vea M, Breckpot K, Kochan G, Escors D. PD1 signal transduction pathways in T cells. Oncotarget. 2017;8(31):51936–45.PubMedPubMedCentralCrossRef
62.
Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 pathway: signaling, cancer, and beyond. Adv Exp Med Biol. 2020;1248:33–59.PubMedCrossRef
63.
Barclay J, Creswell J, Leon J. Cancer immunotherapy and the PD-1/PD-L1 checkpoint pathway. Arch Esp Urol. 2018;71(4):393–9.PubMed
64.
Guzik K, Tomala M, Muszak D, Konieczny M, Hec A, Błaszkiewicz U, Pustuła M, Butera R, Dömling A, Holak TA. Development of the inhibitors that target the PD-1/PD-L1 interaction—a brief look at progress on small molecules, peptides and macrocycles. Molecules. 2019;24(11):2071.PubMedCentralCrossRef
65.
Han Y, Gao Y, He T, Wang D, Guo N, Zhang X, Chen S, Wang H. PD-1/PD-L1 inhibitor screening of caffeoylquinic acid compounds using surface plasmon resonance spectroscopy. Anal Biochem. 2018;547:52–6.PubMedCrossRef
66.
Lin X, Lu X, Luo G, Xiang H. Progress in PD-1/PD-L1 pathway inhibitors: from biomacromolecules to small molecules. Eur J Med Chem. 2020;186:111876.PubMedCrossRef
67.
68.
Lee HT, Lee SH, Heo Y-S. Molecular interactions of antibody drugs targeting PD-1, PD-L1, and CTLA-4 in immuno-oncology. Molecules. 2019;24(6):1190.PubMedCentralCrossRef
69.
70.
Concepcion J, Witte K, Wartchow C, Choo S, Yao D, Persson H, Wei J, Li P, Heidecker B, Ma W, et al. Label-free detection of biomolecular interactions using BioLayer interferometry for kinetic characterization. Comb Chem High Throughput Screen. 2009;12(8):791–800.PubMedCrossRef
71.
Ghai R, Falconer RJ, Collins BM. Applications of isothermal titration calorimetry in pure and applied research—survey of the literature from 2010. J Mol Recognit. 2012;25(1):32–52.PubMedCrossRef
72.
Pascolutti R, Sun X, Kao J, Maute RL, Ring AM, Bowman GR, Kruse AC. Structure and dynamics of PD-L1 and an ultra-high-affinity PD-1 Receptor Mutant. Structure. 2016;24(10):1719–28.PubMedPubMedCentralCrossRef
73.
Wienken CJ, Baaske P, Rothbauer U, Braun D, Duhr S. Protein-binding assays in biological liquids using microscale thermophoresis. Nat Commun. 2010;1:100.PubMedCrossRef
74.
Jerabek-Willemsen M, Wienken CJ, Braun D, Baaske P, Duhr S. Molecular interaction studies using microscale thermophoresis. Assay Drug Dev Technol. 2011;9(4):342–53.PubMedPubMedCentralCrossRef
75.
Gontier A, Varela PF, Nemoz C, Ropars V, Aumont-Nicaise M, Desmadril M, Charbonnier J-B. Measurements of protein–DNA complexes interactions by isothermal titration calorimetry (ITC) and microscale thermophoresis (MST). In: Multiprotein complexes. Springer; 2021. pp. 125–43.
76.
Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, Cammer M, Chen L, Zhang ZY, Edidin MA, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity. 2004;20(3):337–47.PubMedCrossRef
77.
Niesen FH, Berglund H, Vedadi M. The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability. Nat Protoc. 2007;2(9):2212.PubMedCrossRef
78.
Matulis D, Kranz JK, Salemme FR, Todd MJ. Thermodynamic stability of carbonic anhydrase: measurements of binding affinity and stoichiometry using ThermoFluor. Biochemistry. 2005;44(13):5258–66.PubMedCrossRef
79.
Zak KM, Grudnik P, Guzik K, Zieba BJ, Musielak B, Dömling A, Dubin G, Holak TA. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). Oncotarget. 2016;7(21):30323.PubMedPubMedCentralCrossRef
80.
Askin SP, Bond TE, Schaeffer PM. Green fluorescent protein-based assays for high-throughput functional characterization and ligand-binding studies of biotin protein ligase. Anal Methods. 2016;8(2):418–24.CrossRef
81.
82.
Zhou K, Lu J, Yin X, Xu H, Li L, Ma B. Structure-based derivation and intramolecular cyclization of peptide inhibitors from PD-1/PD-L1 complex interface as immune checkpoint blockade for breast cancer immunotherapy. Biophys Chem. 2019;253:106213.PubMedCrossRef
83.
Moerke NJ. Fluorescence polarization (FP) assays for monitoring peptide-protein or nucleic acid-protein binding. Curr Protoc Chem Biol. 2009;1(1):1–15.PubMedCrossRef
84.
Jeong W-J, Bu J, Han Y, Drelich AJ, Nair A, Král P, Hong S. Nanoparticle conjugation stabilizes and multimerizes β-hairpin peptides to effectively target PD-1/PD-L1 β-sheet-rich interfaces. J Am Chem Soc. 2020;142(4):1832–7.PubMedCrossRef
85.
Musielak B, Janczyk W, Rodriguez I, Plewka J, Sala D, Magiera-Mularz K, Holak T. Competition NMR for detection of hit/lead inhibitors of protein-protein interactions. Molecules. 2020;25(13):3017.PubMedCentralCrossRef
86.
Babaoglu K, Shoichet BK. Deconstructing fragment-based inhibitor discovery. Nat Chem Biol. 2006;2(12):720–3.PubMedCrossRef
87.
Fielding L. NMR methods for the determination of protein-ligand dissociation constants. Curr Top Med Chem. 2003;3(1):39–53.PubMedCrossRef
88.
Perry E, Mills JJ, Zhao B, Wang F, Sun Q, Christov PP, Tarr JC, Rietz TA, Olejniczak ET, Lee T, et al. Fragment-based screening of programmed death ligand 1 (PD-L1). Bioorg Med Chem Lett. 2019;29(6):786–90.PubMedPubMedCentralCrossRef
89.
Zak KM, Grudnik P, Guzik K, Zieba BJ, Musielak B, Domling A, Dubin G, Holak TA. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). Oncotarget. 2016;7(21):30323–35.PubMedPubMedCentralCrossRef
90.
Skinner AL, Laurence JS. High-field solution NMR spectroscopy as a tool for assessing protein interactions with small molecule ligands. J Pharm Sci. 2008;97(11):4670–95.PubMedPubMedCentralCrossRef
91.
Lequin RM. Enzyme immunoassay (EIA)/enzyme-linked immunosorbent assay (ELISA). Clin Chem. 2005;51(12):2415–8.PubMedCrossRef
92.
Cauchon E, Liu S, Percival MD, Rowland SE, Xu D, Binkert C, Strickner P, Falgueyret J-P. Development of a homogeneous immunoassay for the detection of angiotensin I in plasma using AlphaLISA acceptor beads technology. Anal Biochem. 2009;388(1):134–9.PubMedCrossRef
93.
Cheng Z-J, Karassina N, Grailer J, Hartnett J, Fan F, Cong M. novel PD-1 blockade bioassay to assess therapeutic antibodies in PD-1 and PD-L1 immunotherapy programs. Cancer Res. 2015;75(Suppl):abstr 5440.CrossRef
94.
Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999;18(49):6853–66.PubMedCrossRef
95.
96.
Zhou X, Mehta S, Zhang J. Genetically encodable fluorescent and bioluminescent biosensors light up signaling networks. Trends Biochem Sci. 2020;45:889–905.PubMedCrossRefPubMedCentral
97.
Davari K, Holland T, Prassmayer L, Longinotti G, Ganley K, Pechilis L, Diaconu I, Nambiar P, Magee M, Schendel D. 161 Development of a CD8 co-receptor independent T cell receptor specific for tumor-associated antigen MAGE-A4 for next generation T cell-based immunotherapy. In: BMJ specialist journals; 2020.
98.
Mizuno R, Sugiura D, Shimizu K, Maruhashi T, Watada M, Okazaki IM, Okazaki T. PD-1 primarily targets TCR signal in the inhibition of functional T cell activation. Front Immunol. 2019;10:630.PubMedPubMedCentralCrossRef
99.
Hsieh Y-T, Aggarwal P, Cirelli D, Gu L, Surowy T, Mozier NM. Characterization of FcγRIIIA effector cells used in in vitro ADCC bioassay: comparison of primary NK cells with engineered NK-92 and Jurkat T cells. J Immunol Methods. 2017;441:56–66.PubMedCrossRef
100.
Abraham RT, Weiss A. Jurkat T cells and development of the T-cell receptor signalling paradigm. Nat Rev Immunol. 2004;4(4):301–8.PubMedCrossRef
101.
Versteven M, Van den Bergh JMJ, Broos K, Fujiki F, Campillo-Davo D, De Reu H, Morimoto S, Lecocq Q, Keyaerts M, Berneman Z, et al. A versatile T cell-based assay to assess therapeutic antigen-specific PD-1-targeted approaches. Oncotarget. 2018;9(45):27797–808.PubMedPubMedCentralCrossRef
102.
Zhai W, Zhou X, Du J, Gao Y. In vitro assay for the development of small molecule inhibitors targeting PD-1/PD-L1. Methods Enzymol. 2019;629:361–81.PubMedCrossRef
103.
Zhang R, Zhu Z, Lv H, Li F, Sun S, Li J, Lee CS. Immune checkpoint blockade mediated by a small-molecule nanoinhibitor targeting the PD-1/PD-L1 pathway synergizes with photodynamic therapy to elicit antitumor immunity and antimetastatic effects on breast cancer. Small. 2019;15(49):1903881.CrossRef
104.
Konieczny M, Musielak B, Kocik J, Skalniak L, Sala D, Czub M, Magiera-Mularz K, Rodriguez I, Myrcha M, Stec M. Di-bromo-based small-molecule inhibitors of the PD-1/PD-L1 immune checkpoint. J Med Chem. 2020;63(19):11271–85.PubMedPubMedCentralCrossRef
105.
106.
Vareki SM, Garrigós C, Duran I. Biomarkers of response to PD-1/PD-L1 inhibition. Crit Rev Oncol Hematol. 2017;116:116–24.CrossRef
107.
Yadav J, Dikshit N, Ismaeel S, Qadri A. Innate activation of IFN-γ—iNOS axis during infection with salmonella represses the ability of T cells to produce IL-2. Front Immunol. 2020;11:514.PubMedPubMedCentralCrossRef
108.
van Asten SD, de Groot R, van Loenen MM, Castenmiller SM, de Jong J, Monkhorst K, Haanen JB, Amsen D, Bex A, Spaapen RM. T cells expanded from renal cell carcinoma display tumor-specific CD137 expression but lack significant IFN-γ, TNF-α or IL-2 production. OncoImmunology. 2021;10(1):1860482.PubMedPubMedCentralCrossRef
109.
110.
Fessas P, Possamai LA, Clark J, Daniels E, Gudd C, Mullish BH, Alexander JL, Pinato DJ. Immunotoxicity from checkpoint inhibitor therapy: clinical features and underlying mechanisms. Immunology. 2020;159(2):167–77.PubMedCrossRef
111.
Jiao P, Geng Q, Jin P, Su G, Teng H, Dong J, Yan B. Small molecules as PD-1/PD-L1 pathway modulators for cancer immunotherapy. Curr Pharm Des. 2018;24(41):4911–20.PubMedCrossRef
112.
Sun H, Chen D, Zhan S, Wu W, Xu H, Luo C, Su H, Feng Y, Shao W, Wan A, et al. Design and discovery of natural cyclopeptide skeleton based programmed death ligand 1 inhibitor as immune modulator for cancer therapy. J Med Chem. 2020;63(19):11286–301.PubMedCrossRef
113.
Patil SP, Yoon SC, Aradhya AG, Hofer J, Fink MA, Enley ES, Fisher JE, Herb MC, Klingos A, Proulx JT, et al. Macrocyclic Compounds from ansamycin antibiotic class as inhibitors of PD1-PDL1 protein-protein interaction. Chem Pharm Bull (Tokyo). 2018;66(8):773–8.CrossRef
114.
Kim JH, Kim YS, Choi JG, Li W, Lee EJ, Park JW, Song J, Chung HS. Kaempferol and its glycoside, kaempferol 7-O-rhamnoside, inhibit PD-1/PD-L1 interaction in vitro. Int J Mol Sci. 2020;21(9):3239.PubMedCentralCrossRef
115.
Choi JG, Kim YS, Kim JH, Kim TI, Li W, Oh TW, Jeon CH, Kim SJ, Chung HS. Anticancer effect of Salvia plebeia and its active compound by improving T-cell activity via blockade of PD-1/PD-L1 interaction in humanized PD-1 mouse model. Front Immunol. 2020;11:598556.PubMedPubMedCentralCrossRef
116.
Li W, Kim TI, Kim JH, Chung HS. Immune checkpoint PD-1/PD-L1 CTLA-4/CD80 are blocked by Rhus verniciflua stokes and its active compounds. Molecules. 2019;24(22):4062.PubMedCentralCrossRef
117.
Bao F, Bai HY, Wu ZR, Yang ZG. Phenolic compounds from cultivated Glycyrrhiza uralensis and their PD-1/PD-L1 inhibitory activities. Nat Prod Res. 2019;35:562–9.PubMedCrossRef
118.
Kim JH, Kim YS, Kim TI, Li W, Mun JG, Jeon HD, Kee JY, Choi JG, Chung HS. Unripe black raspberry (Rubus coreanus Miquel) extract and its constitute, ellagic acid induces T cell activation and antitumor immunity by blocking PD-1/PD-L1 interaction. Foods. 2020;9(11):1590.PubMedCentralCrossRef
119.
Lung J, Hung MS, Lin YC, Hung CH, Chen CC, Lee KD, Tsai YH. Virtual screening and in vitro evaluation of PD-1 dimer stabilizers for uncoupling PD-1/PD-L1 interaction from natural products. Molecules. 2020;25(22):5293.PubMedCentralCrossRef
120.
121.
Soren K, Kabiraj A, Goswami P, Banerjee A, Bandopadhyay R. A breakthrough on cancer therapy by inhibition of negative immune regulation: nobel prize in physiology or medicine 2018. Berlin: Springer; 2020.
Metadata
Title
Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review
Authors
Chang Liu
Navindra P. Seeram
Hang Ma
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-021-01946-4

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Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
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