Novel Small Molecule Inhibitors of Programmed Cell Death (PD)-1, and its Ligand, PD-L1 in Cancer Immunotherapy: A Review Update of Patent Literature

Author(s): Spandana R. Kopalli, Tae-Bong Kang, Kwang-Ho Lee, Sushruta Koppula*.

Journal Name: Recent Patents on Anti-Cancer Drug Discovery

Volume 14 , Issue 2 , 2019

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Abstract:

Background: In the last few decades, cancer immunotherapy has been extensively researched, and novel checkpoint signaling mechanisms involving Programmed Death (PD)-1 and PDLigand 1 (PD-L1) receptors have been targeted. The PD-1/PD-L1 binding and interaction play a critical role in the development of malignancies.

Objective: The present review focuses on recent patents on the pharmacological and biological cancerregulating properties of PD-1/PD-L1 inhibitors involved in immunotherapeutic cancer drug development.

Methods: Thorough patent literature search published during the last seven years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents, to identify PD-1/PD-L1-targeting small molecule immunomodulators.

Results: Several small molecule PD-1/PD-L1 inhibitors were patented for regulation of tumor progression by academic and industry-associated investigators. Most of the claimed patents have been validated and confined to in vitro and in vivo mouse models limiting their entry into clinical settings. Majority of the patents are claimed by the researchers at Aurigene Ltd. (India) on novel peptidomimetic compounds. It is worth to be noted that macrocyclic compounds such as the peptides QP20, HD20, WQ20, SQ20, and CQ-22 from Bristol-Myers Squibb (BMS) Company, biaryl, and heterocyclic derivatives including 1,3-dihydroxy-phenyl compounds were efficient in regulating the PD-1/PD-L1 protein-protein binding and interaction compared to those of the approved monoclonal antibodies.

Conclusion: PD-1/PD-L1 inhibitors show significant anti-cancer responses as stand-alone agents and in combination with other cancer therapies. More efficient experimental studies and clinical trials are necessary to evaluate the host-tumor cells’ interactions. Understanding the cancer microenvironment, and identifying specific biomarkers and X-ray crystalline structures of PD-1/PD-L1 complexes, including molecular and genomic signature studies are essential to determine the feasibility of PD-1/PD-L1 inhibitors for development into drug-like cancer immunotherapeutics.

Keywords: Cancer, immune checkpoints, immunomodulatory, immunotherapy, peptidomimetic, PD-1/PDL-1 signaling.

[1]
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science (New York, NY) 1996; 271(5256): 1734-6.
[2]
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4): 252-64.
[3]
Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science (New York, NY) 2013; 342(6165): 1432-3.
[4]
Page DB, Postow MA, Callahan MK, Allison JP, Wolchok JD. Immune modulation in cancer with antibodies. Annu Rev Med 2014; 65: 185-202.
[5]
Kershaw MH, Westwood JA, Slaney CY, Darcy PK. Clinical application of genetically modified T-cells in cancer therapy. Clin Transl Immunology 2014; 3(5)e16
[6]
Dine J, Gordon R, Shames Y, Kasler MK, Barton-Burke M. Immune Checkpoint Inhibitors: An Innovation in Immunotherapy for the treatment and management of patients with cancer. Asia Pac J Oncol Nurs 2017; 4(2): 127-35.
[7]
Chaplin DD. Overview of the immune response. J Allergy Clin Immunol 2010; 125(2)(Suppl. 2): S3-S23.
[8]
Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: Similarities, differences, and implications of their inhibition. Am J Clin Oncol 2016; 39(1): 98-106.
[9]
Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008; 224: 166-82.
[10]
Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, et al. Expression of programmed death-1 ligands by murine T-cells and APC. J Immunol (Baltimore, Md: 1950). 2002; 169(10): 5538-45.
[11]
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 2012; 4(127)127ra37
[12]
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat Med 2002; 8(8): 793-800.
[13]
Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996; 8(5): 765-72.
[14]
Sunshine J, Taube JM. PD-1/PD-L1 inhibitors. Curr Opin Pharmacol 2015; 23: 32-8.
[15]
Iwai Y, Hamanishi J, Chamoto K, Honjo T. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci 2017; 24(1): 26-32.
[16]
Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol 2011; 29: 235-71.
[17]
Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3(11): 991-8.
[18]
Disis ML. Immune regulation of cancer. J Clin Oncol 2010; 28(29): 4531-8.
[19]
Weinmann H. Cancer immunotherapy: Selected targets and small-molecule modulators. ChemMedChem 2016; 11(5): 450-66.
[20]
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: 677-704.
[21]
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192(7): 1027-34.
[22]
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012; 24(2): 207-12.
[23]
Sui X, Ma J, Han W, Wang X, Fang Y, Li D, et al. The anti-cancer immune response of anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients. Oncotarget 2015; 6(23): 19393-404.
[24]
Dong Y, Sun Q, Zhang X. PD-1 and its ligands are important immune checkpoints in cancer. Oncotarget 2017; 8(2): 2171-86.
[25]
Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol 2006; 27(4): 195-201.
[26]
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): 12293-7.
[27]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005; 23: 515-48.
[28]
Gong J, Chehrazi-Raffle A, Reddi S, Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: A comprehensive review of registration trials and future considerations. J Immunother Cancer 2018; 6(1): 8-16.
[29]
Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: Mechanisms of action, efficacy, and limitations. Front Oncol 2018; 8: 86-93.
[30]
Hoelder S, Clarke PA, Workman P. Discovery of small molecule cancer drugs: successes, challenges and opportunities. Mol Oncol 2012; 6(2): 155-76.
[31]
Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014; 515: 577-83.
[32]
Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: A comprehensive review. Eur J Cancer 2016; 54: 139-48.
[33]
Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: New immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res 2013; 19(19): 5300-9.
[34]
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144(5): 646-74.
[35]
Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, et al. PD-1 and PD-L1 Checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome. Front Pharmacol 2017; 8: 561-8.
[36]
Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 2015; 26(12): 2375-91.
[37]
Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov 2010; 9(10): 767-74.
[38]
Harding FA, Stickler MM, Razo J, DuBridge RB. The immunogenicity of humanized and fully human antibodies: Residual immunogenicity resides in the CDR regions. MAbs 2010; 2(3): 256-65.
[39]
Sharpe AH, Butte MJ, Oyama S. Modulators of immunoinhibitory receptor PD-1, and methods of use thereof. WO2011082400 (2011).
[40]
Casini A, Scozzafava A, Mastrolorenzo A, Supuran LT. Sulfonamides and sulfonylated derivatives as anti-cancer agents. Curr Cancer Drug Targets 2002; 2(1): 55-75.
[41]
Sasikumar PGN, Ramachandra M, Vadlamani S K, et al. Immunosuppression modulating compounds. US20110318373 (2011).
[42]
Sasikumar PGN, Ramachandra M, Vadlamani SK, et al. Immunosuppression modulating compounds. WO2011161699 (2011).
[43]
Sasikumar PGN, Ramachandra M, Vadlamani S K, Shrimali KR, Subbarao K. Therapeutic compounds for immunomodulation. WO2012168944 (2012).
[44]
Sasikumar PGN, Ramachandra M, Naremaddepalli SSS. Peptidomimetic compounds as immunomodulators. WO2013132317 (2013).
[45]
Sasikumar PGN, Ramachandra M, Naremaddepalli SSS. 1,3,4-Oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators. WO2015033301 (2015).
[46]
Sasikumar PGN, Ramachandra M. Immunomodulating cyclic compounds from the bc loop of human PD1. WO2013144704 (2013) & US20180086726 (2018).
[47]
Sasikumar PGN, Ramachandra M, Naremaddepalli SSS. 1,3,4-oxadiazole and thiadiazole compounds as immunomodulators. WO2016142852 (2016).
[48]
Sasikumar PGN, Ramachandra M, Naremaddepalli SSS. 1,2,4-Oxadiazole derivatives as immunomodulators. US20180072689 (2018).
[49]
Lu L, Qian D Q, Wu L, Yao W. Heterocyclic compounds as immunomodulators. WO2017205464 (2017).
[50]
Xiao K, Zhang F, Wu L, Yao W. Heterocyclic compounds as immunomodulators. WO2017222976 (2017).
[51]
Yu Z, Wu L, Yao W. Heterocyclic compounds as immunomodulators. WO2018013789 (2018).
[52]
Wu L, Zhang F, Mei S, Yao W. Heterocyclic compounds as immunomodulators. US20180057486 (2018).
[53]
Lange C, Malathong V, McMurtrie DJ, et al. Immunomodulator compounds. US20180008554 (2018).
[54]
Gutierrez GM, Vinayaka K, Pannucci J. Ayala, R. PD-1 peptide inhibitors. WO2018053218 (2018).
[55]
Tzeng HT, Tsai HF, Liao HJ, Lin YJ, Chen L, Chen PJ, et al. PD-1 blockage reverses immune dysfunction and hepatitis B viral persistence in a mouse animal model. PLoS One 2012; 7(6)e39179
[56]
Ye B, Liu X, Li X, Kong H, Tian L, Chen Y. T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. Cell Death Dis 2015; 6e1694
[57]
Kaufmann DE, Walker BD. PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. J Immunol 2009; 182(10): 5891-7.
[58]
Mukhopadhyay A, Hanold LE, Thayele Purayil H, Gisemba SA, Senadheera SN, Aldrich JV. Macrocyclic peptides decrease c-Myc protein levels and reduce prostate cancer cell growth. Cancer Biol Ther 2017; 18(8): 571-83.
[59]
Miller MM, Mapelli C, Allen MP, et al. Macrocyclic inhibitors of the PD-1/PD-L1 and CD80(b7- 1)/PD-L1 protein/protein interactions. WO2014151634 (2014) & US9850283 (2017).
[60]
Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T-cells during chronic viral infection. Nature 2006; 439(7077): 682-7.
[61]
Chupak LS, Zheng X. Compounds useful as immunomodulators. WO2015034820 (2015).
[62]
Yeung KS, Grant-Young KA, Zhu J, et al. 1,3-dihydroxy-phenyl derivatives useful as immunomodulators. WO2018009505 (2018).
[63]
Yeung KS, Grant-Young KA, Zhu J, et al. Scola, P.M. Biaryl compounds useful as immunomodulators. WO2018044963 (2018).
[64]
Dömling A. Inhibitors of the PD-1/PD-L1 protein/protein interaction. WO2017118762 (2017).
[65]
Chupak LS, Ding M, Martin SW, et al. Compounds useful as immunomodulators. WO2015160641 (2015).
[66]
Zak KM, Grudnik P, Guzik K, Zieba BJ, Musielak B, Dömling A, et al. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). Oncotarget 2016; 7(21): 30323-35.
[67]
Zak KM, Kitel R, Przetocka S, et al. Structure of the complex of human programmed death-1 (PD-1) and its ligand PD-L1. Structure 2015; 23: 1-8.
[68]
Wang M. Symmetric or semi-symmetric compounds useful as immunomodulators. WO2018026971 (2018).
[69]
Chang HN, Liu BY, Qi YK, Zhou Y, Chen YP, Pan KM, et al. Blocking of the PD-1/PD-L1 Interaction by a D-Peptide Antagonist for Cancer Immunotherapy. Angew Chem Int Ed Engl 2015; 54(40): 11760-4.
[70]
Hanley RP, Horvath S, An J, Hof F, Wulff JE. Salicylates are interference compounds in TR-FRET assays. Bioorg Med Chem Lett 2016; 26(3): 973-7.
[71]
Strebhardt K, Ullrich A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer 2008; 8(6): 473-80.
[72]
Karlitepe A, Ozalp O, Avci CB. New approaches for cancer immunotherapy. Tumour Biol 2015; 36(6): 4075-8.
[73]
Patel JD, Krilov L, Adams S, Aghajanian C, Basch E, Brose MS, et al. Clinical cancer advances: Annual report on progress against cancer from the American society of clinical oncology. J Clin Oncol 2014; 32(2): 129-60.
[74]
Zeng C, Wen W, Morgans AK, Pao W, Shu XO, Zheng W. Disparities by race, age, and sex in the improvement of survival for major cancers: Results from the National Cancer Institute surveillance, epidemiology, and end results (SEER) program in the United States, 1990 to 2010. JAMA Oncol 2015; 1(1): 88-96.
[75]
Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 2018; 8(9): 1069-86.
[76]
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4): 252-64.
[77]
Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015; 348: 56-61.
[78]
Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015; 27: 450-61.
[79]
Kyi C, Postow MA. Checkpoint blocking antibodies in cancer immunotherapy. FEBS Lett 2014; 588(2): 368-76.
[80]
Carvalho S, Levi-Schaffer F, Sela M, Yarden Y. Immunotherapy of cancer: from monoclonal to oligoclonal cocktails of anti-cancer antibodies: IUPHAR Review 18. Br J Pharmacol 2016; 173(9): 1407-24.
[81]
Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res 2008; 14(10): 3044-51.
[82]
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366(26): 2455-65.
[83]
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369(2): 134-44.
[84]
Guo L, Zhang H, Chen B. Nivolumab as programmed death-1 (PD-1) inhibitor for targeted immunotherapy in tumor. J Cancer 2017; 8(3): 410-6.
[85]
Wang X, Huang S, Zhang Y, Zhu L, Wu X. The application and mechanism of PD pathway blockade for cancer therapy. Postgrad Med J 2018; 94(1107): 53-9.
[86]
Li K, Tian H. Development of small-molecule immune checkpoint inhibitors of PD-1/PD-L1 as a new therapeutic strategy for tumor immunotherapy. J Drug Target 2018; 1-13.
[87]
Yang J, Hu L. Immunomodulators targeting the PD-1/PD-L1 protein-protein interaction: From antibodies to small molecules. Med Res Rev 2018; 1-37.
[88]
Sasikumar PG, Ramachandra M. Small-molecule immune checkpoint inhibitors targeting PD-1/PD-L1 and other emerging checkpoint pathways. BioDrugs 2018; 32(5): 481-97.
[89]
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.
[90]
Zarganes-Tzitzikas T, Konstantinidou M, Gao Y, 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; 26(9): 973-7.
[91]
Cheng X, Veverka V, Radhakrishnan A, Waters LC, Muskett FW, Morgan SH, et al. Structure and interactions of the human programmed cell death 1 receptor. J Biol Chem 2013; 288(17): 11771-85.
[92]
Zak KM, Grudnik P, Magiera K, Dömling A, Dubin G, Holak TA. Structural biology of the immune checkpoint receptor PD-1 and its ligands PD-L1/PD-L2. Structure 2017; 25(8): 1163-74.
[93]
Chae YK, Arya A, Iams W, Cruz MR, Chandra S, Choi J, et al. Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC). J Immunother Cancer 2018; 6(1): 39-42.
[94]
Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 2014; 20(19): 5064-74.
[95]
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res 2007; 13(6): 1757-61.
[96]
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014; 515(7528): 568-71.
[97]
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer Immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348(6230): 124-8.
[98]
Simon S, Labarriere N. PD-1 expression on tumor-specific T cells: Friend or foe for immunotherapy? Oncoimmunol 2018; 7(1)e1364828
[99]
Zerdes I, Matikas A, Bergh J, Rassidakis GZ, Foukakis T. Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations. Oncogene 2018; 37(34): 4639-61.


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VOLUME: 14
ISSUE: 2
Year: 2019
Page: [100 - 112]
Pages: 13
DOI: 10.2174/1574892813666181029142812
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