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Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor
Blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with antibodies, small molecules could demonstrate i...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9394386/ https://www.ncbi.nlm.nih.gov/pubmed/35254416 http://dx.doi.org/10.1158/2159-8290.CD-21-1156 |
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author | Koblish, Holly K. Wu, Liangxing Wang, Liang-Chuan S. Liu, Phillip C.C. Wynn, Richard Rios-Doria, Jonathan Spitz, Susan Liu, Hao Volgina, Alla Zolotarjova, Nina Kapilashrami, Kanishk Behshad, Elham Covington, Maryanne Yang, Yan-ou Li, Jingwei Diamond, Sharon Soloviev, Maxim O'Hayer, Kevin Rubin, Stephen Kanellopoulou, Chrysi Yang, Gengjie Rupar, Mark DiMatteo, Darlise Lin, Luping Stevens, Christina Zhang, Yue Thekkat, Pramod Geschwindt, Ryan Marando, Cindy Yeleswaram, Swamy Jackson, Jeff Scherle, Peggy Huber, Reid Yao, Wenqing Hollis, Gregory |
author_facet | Koblish, Holly K. Wu, Liangxing Wang, Liang-Chuan S. Liu, Phillip C.C. Wynn, Richard Rios-Doria, Jonathan Spitz, Susan Liu, Hao Volgina, Alla Zolotarjova, Nina Kapilashrami, Kanishk Behshad, Elham Covington, Maryanne Yang, Yan-ou Li, Jingwei Diamond, Sharon Soloviev, Maxim O'Hayer, Kevin Rubin, Stephen Kanellopoulou, Chrysi Yang, Gengjie Rupar, Mark DiMatteo, Darlise Lin, Luping Stevens, Christina Zhang, Yue Thekkat, Pramod Geschwindt, Ryan Marando, Cindy Yeleswaram, Swamy Jackson, Jeff Scherle, Peggy Huber, Reid Yao, Wenqing Hollis, Gregory |
author_sort | Koblish, Holly K. |
collection | PubMed |
description | Blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe the identification and characterization of INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In vitro, INCB086550 selectively and potently blocked the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, and induced stimulation-dependent cytokine production in primary human immune cells. In vivo, INCB086550 reduced tumor growth in CD34(+) humanized mice and induced T-cell activation gene signatures, consistent with PD-L1/PD-1 pathway blockade. Preliminary data from an ongoing phase I study confirmed PD-L1/PD-1 blockade in peripheral blood cells, with increased immune activation and tumor growth control. These data support continued clinical evaluation of INCB086550 as an alternative to antibody-based therapies. SIGNIFICANCE: We have identified a potent small-molecule inhibitor of PD-L1, INCB086550, which has biological properties similar to PD-L1/PD-1 monoclonal antibodies and may represent an alternative to antibody therapy. Preliminary clinical data in patients demonstrated increased immune activation and tumor growth control, which support continued clinical evaluation of this approach. See related commentary by Capparelli and Aplin, p. 1413. This article is highlighted in the In This Issue feature, p. 1397 |
format | Online Article Text |
id | pubmed-9394386 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-93943862023-01-05 Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor Koblish, Holly K. Wu, Liangxing Wang, Liang-Chuan S. Liu, Phillip C.C. Wynn, Richard Rios-Doria, Jonathan Spitz, Susan Liu, Hao Volgina, Alla Zolotarjova, Nina Kapilashrami, Kanishk Behshad, Elham Covington, Maryanne Yang, Yan-ou Li, Jingwei Diamond, Sharon Soloviev, Maxim O'Hayer, Kevin Rubin, Stephen Kanellopoulou, Chrysi Yang, Gengjie Rupar, Mark DiMatteo, Darlise Lin, Luping Stevens, Christina Zhang, Yue Thekkat, Pramod Geschwindt, Ryan Marando, Cindy Yeleswaram, Swamy Jackson, Jeff Scherle, Peggy Huber, Reid Yao, Wenqing Hollis, Gregory Cancer Discov Research Articles Blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe the identification and characterization of INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In vitro, INCB086550 selectively and potently blocked the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, and induced stimulation-dependent cytokine production in primary human immune cells. In vivo, INCB086550 reduced tumor growth in CD34(+) humanized mice and induced T-cell activation gene signatures, consistent with PD-L1/PD-1 pathway blockade. Preliminary data from an ongoing phase I study confirmed PD-L1/PD-1 blockade in peripheral blood cells, with increased immune activation and tumor growth control. These data support continued clinical evaluation of INCB086550 as an alternative to antibody-based therapies. SIGNIFICANCE: We have identified a potent small-molecule inhibitor of PD-L1, INCB086550, which has biological properties similar to PD-L1/PD-1 monoclonal antibodies and may represent an alternative to antibody therapy. Preliminary clinical data in patients demonstrated increased immune activation and tumor growth control, which support continued clinical evaluation of this approach. See related commentary by Capparelli and Aplin, p. 1413. This article is highlighted in the In This Issue feature, p. 1397 American Association for Research 2022-06-02 2022-03-07 /pmc/articles/PMC9394386/ /pubmed/35254416 http://dx.doi.org/10.1158/2159-8290.CD-21-1156 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Research Articles Koblish, Holly K. Wu, Liangxing Wang, Liang-Chuan S. Liu, Phillip C.C. Wynn, Richard Rios-Doria, Jonathan Spitz, Susan Liu, Hao Volgina, Alla Zolotarjova, Nina Kapilashrami, Kanishk Behshad, Elham Covington, Maryanne Yang, Yan-ou Li, Jingwei Diamond, Sharon Soloviev, Maxim O'Hayer, Kevin Rubin, Stephen Kanellopoulou, Chrysi Yang, Gengjie Rupar, Mark DiMatteo, Darlise Lin, Luping Stevens, Christina Zhang, Yue Thekkat, Pramod Geschwindt, Ryan Marando, Cindy Yeleswaram, Swamy Jackson, Jeff Scherle, Peggy Huber, Reid Yao, Wenqing Hollis, Gregory Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor |
title | Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor |
title_full | Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor |
title_fullStr | Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor |
title_full_unstemmed | Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor |
title_short | Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor |
title_sort | characterization of incb086550: a potent and novel small-molecule pd-l1 inhibitor |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9394386/ https://www.ncbi.nlm.nih.gov/pubmed/35254416 http://dx.doi.org/10.1158/2159-8290.CD-21-1156 |
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