Small-Molecule Immune Checkpoint Inhibitors Targeting PD-1/PD-L1 and Other Emerging Checkpoint Pathways

BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
Pottayil G Sasikumar, Murali Ramachandra

Abstract

Advances in harnessing the immune system for cancer treatment have been spectacular in recent years as witnessed by the approval of a number of antibodies targeting the PD-1/PD-L1 immune checkpoint pathway spanning an expanding list of indications. However, it is well recognized that while these antibodies show impressive clinical activity, they suffer from shortcomings including the failure to show response in a majority of patients, their need to be administered by intravenous injection, and immune-related adverse events due to the breaking of immune self-tolerance. Small-molecule-based therapeutic approaches offer the potential to address the shortcomings of these antibody-based checkpoint inhibitors. In the first part of this review, we discuss the rationale for small-molecule-based checkpoint therapy followed by efforts on the discovery of small-molecule-based approaches targeting the PD-1/PD-L1 axis and other immune checkpoint pathways. In the latter part of the article, we describe small-molecule inhibitors simultaneously targeting two non-redundant checkpoint inhibitor pathways as an approach to improve the response rate. A brief review of the progress of an oral small-molecule checkpoint inhibitor currently in clinical...Continue Reading

References

Feb 22, 2008·Proceedings of the National Academy of Sciences of the United States of America·David Yin-Wei LinDavid N Garboczi
Aug 12, 2008·Bioorganic & Medicinal Chemistry Letters·Jason D HughesYao Zhang
Jun 3, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Julie R BrahmerSuzanne L Topalian
Mar 9, 2011·The Journal of Experimental Medicine·Li WangRandolph J Noelle
Jul 9, 2011·Nature Immunology·E John Wherry
Jul 20, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Dallas B FliesLieping Chen
Mar 23, 2012·Nature Reviews. Cancer·Drew M Pardoll
Mar 28, 2012·Proceedings of the National Academy of Sciences of the United States of America·Badreddin EdrisMatt van de Rijn
Jun 5, 2012·The New England Journal of Medicine·Suzanne L TopalianMario Sznol
Jun 5, 2012·The New England Journal of Medicine·Julie R BrahmerJon M Wigginton
Aug 30, 2012·Journal of Pharmaceutical Sciences·Klara ValkoDino Montanari
Nov 12, 2013·Trends in Immunology·Andrea Schietinger, Philip D Greenberg
Dec 21, 2013·Science·Jennifer Couzin-Frankel
Apr 3, 2014·Cancer Research·J Louise LinesRandolph Noelle
Feb 18, 2015·Mutagenesis·Tala ShekarianAurélien Marabelle
Apr 10, 2015·British Journal of Cancer·B Homet Moreno, A Ribas
Sep 16, 2015·Annals of Oncology : Official Journal of the European Society for Medical Oncology·J NaidooJ D Wolchok
Jun 29, 2016·Immunotherapy·Hampig Raphael Kourie, Jean Klastersky
Nov 17, 2016·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Daphne Day, Aaron R Hansen
Nov 20, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Penka S PetrovaRobert A Uger
Mar 25, 2017·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Wolfram C M DempkeStephen P Dale
Jun 28, 2017·Immunotherapy·Andrew W HahnNeeraj Agarwal
Aug 5, 2017·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Hojabr KakavandRichard A Scolyer
Sep 8, 2017·Angewandte Chemie·Katarzyna Magiera-MularzTad A Holak
Nov 22, 2017·Proceedings of the National Academy of Sciences of the United States of America·Nan Guo RingIrving L Weissman
Dec 6, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Franz Villarroel-EspindolaKurt A Schalper
Dec 8, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Denis L JardimRazelle Kurzrock
Jan 4, 2018·Blood Advances·Reid W MerrymanScott J Rodig
Jan 10, 2018·The Journal of Immunology : Official Journal of the American Association of Immunologists·Martin W LaFleurArlene H Sharpe
Feb 1, 2018·Therapeutic Advances in Medical Oncology·Irene Moya-HornoRafael Rosell
Apr 11, 2018·Oncoimmunology·C Bryce Johnson, Shwe Y Win
May 2, 2018·Trends in Cancer·Xavier Romero Ros, Louis Vermeulen
Jun 5, 2018·Chinese Journal of Cancer Research = Chung-kuo Yen Cheng Yen Chiu·Mengjia SongYi Zhang

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Citations

Aug 29, 2019·Scientific Reports·Aravindhan GanesanKhaled Barakat
Jan 11, 2020·Proceedings of the National Academy of Sciences of the United States of America·Benjamin T SlaterYong Xiong
Sep 8, 2020·Cell Communication and Signaling : CCS·Xiuman ZhouYanfeng Gao
Aug 4, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bogdan MusielakJacek Plewka
Sep 9, 2020·ELife·Sansana Sawasdikosol, Steven Burakoff
Sep 29, 2020·Drug Design, Development and Therapy·Leilei AiXiaochun Yang
May 6, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nam-Hui YimHwan-Suck Chung
Jan 23, 2021·Expert Opinion on Drug Delivery·Andrew S MikhailBradford J Wood
Nov 21, 2020·International Journal of Molecular Sciences·Jiji V D AttiaDaniëlle Krijgsman
Nov 17, 2020·Drug Discovery Today·Wei-Bang YuJin-Jian Lu
Apr 4, 2021·International Journal of Molecular Sciences·Alexander C ChaconPeter A Prieto
Jun 10, 2021·Communications Biology·Pottayil G SasikumarMurali Ramachandra
Aug 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Edyta ZylaGrzegorz Dubin
Aug 16, 2019·ACS Medicinal Chemistry Letters·Derek J BlevinsJeremy E Wulff

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Methods Mentioned

BETA
transgenic
homogeneous time resolved fluorescence
phage display

Software Mentioned

VISTA

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