PD-1 derived CA-170 is an oral immune checkpoint inhibitor that exhibits preclinical anti-tumor efficacy.

Communications Biology
Pottayil G SasikumarMurali Ramachandra

Abstract

Small molecule immune checkpoint inhibitors targeting PD-1 and other pathways may offer advantages including ease of dosing, ability to manage immune-related adverse events (irAEs) due to their shorter pharmacokinetic exposure and opportunity to target more than one pathway for improving efficacy. Here we describe the identification and characterization of CA-170, an amino acid inspired small molecule inhibitor of PD-L1 and VISTA derived from the interface of PD-1 and PD-L1. CA-170 exhibited potent rescue of proliferation and effector functions of T cells inhibited by PD-L1/L2 and VISTA with selectivity over other immune checkpoint proteins as well as a broad panel of receptors and enzymes. Observed blocking of PD-L1 signaling and binding to PD-L1 in the cellular context without preventing the assembly of PD-1:PD-L1 complex support the formation of a defective ternary complex as the mechanism of action of CA-170. Oral administration of CA-170 resulted in increased proliferation and activation of T cells in the tumor, and significant anti-tumor efficacy in a number of immunocompetent mouse tumor models either as a single agent or in combination with approved therapeutics. These results prompted the advancement of CA-170 to human...Continue Reading

References

Mar 26, 2002·Nature Reviews. Immunology·Arlene H Sharpe, Gordon J Freeman
Jul 18, 2002·Nature Reviews. Drug Discovery·Maurizio PellecchiaKurt Wüthrich
Jun 18, 2005·Genome Biology·Mary CollinsBeatriz M Carreno
Feb 22, 2008·Proceedings of the National Academy of Sciences of the United States of America·David Yin-Wei LinDavid N Garboczi
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
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
Apr 3, 2014·Cancer Research·J Louise LinesRandolph Noelle
Jun 5, 2014·Annual Review of Biophysics·Darón I Freedberg, Philipp Selenko
May 13, 2015·Proceedings of the National Academy of Sciences of the United States of America·Jun LiuLi Wang
Nov 21, 2015·Cancer Research·Larysa V YuzefovychLyudmila I Rachek
Mar 16, 2016·Nature Reviews. Clinical Oncology·Danny N KhalilJedd D Wolchok
Nov 28, 2017·Angewandte Chemie·Markella KonstantinidouAlexander Dömling
Dec 6, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Franz Villarroel-EspindolaKurt A Schalper
Sep 1, 2018·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Pottayil G Sasikumar, Murali Ramachandra
Oct 4, 2018·Nature·Heidi LedfordMatthew Warren
Apr 25, 2019·Molecular Cancer Therapeutics·Pottayil G SasikumarMurali Ramachandra
Jul 31, 2019·Journal of Magnetic Resonance·Gregg Siegal, Philipp Selenko
Aug 4, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bogdan MusielakJacek Plewka
Aug 16, 2019·ACS Medicinal Chemistry Letters·Derek J BlevinsJeremy E Wulff
Sep 21, 2019·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Stephanie MullerJennifer L Sauter
Oct 16, 2019·Nature Immunology·Lawrence P AndrewsDario A A Vignali
Nov 30, 2019·Cancer Immunology, Immunotherapy : CII·Liju ZongYang Xiang
Feb 1, 2020·Oncoimmunology·Isaure VanmeerbeekAbhishek D Garg
Mar 11, 2020·Acta Pharmacologica Sinica·Qian WuJi Cao
Mar 12, 2020·Cancer Research·Linlin SunMien-Chie Hung
Apr 2, 2020·Journal of Hematology & Oncology·Sha-Sha ChengDik-Lung Ma

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Citations

Oct 13, 2021·Current Opinion in Oncology·Ling PengZhentao Yu

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