Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors

Marta A Ważyńska; Roberto Butera; Marta Requesens; Annechien Plat; Tryfon Zarganes-Tzitzikas; Constantinos G Neochoritis; Jacek Plewka; Lukasz Skalniak; Justyna Kocik-Krol; Bogdan Musielak; Katarzyna Magiera-Mularz; Ismael Rodriguez; Simon N Blok; Marco de Bruyn; Hans W Nijman; Philip H Elsinga; Tad A Holak; Alexander Dömling

doi:10.1021/acs.jmedchem.3c00254

Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors

Marta A Ważyńska, Roberto Butera, Marta Requesens, Annechien Plat, Tryfon Zarganes-Tzitzikas, Constantinos G Neochoritis, Jacek Plewka, Lukasz Skalniak, Justyna Kocik-Krol, Bogdan Musielak, Katarzyna Magiera-Mularz, Ismael Rodriguez, Simon N Blok, Marco de Bruyn, Hans W Nijman, Philip H Elsinga, Tad A Holak, Alexander Dömling^*

^*Corresponding author for this work

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Abstract

In search of a potent small molecular PD-L1 inhibitor, we designed and synthesized a compound based on a 2-hydroxy-4-phenylthiophene-3-carbonitrile moiety. Ligand's performance was tested in vitro and compared side-by-side with a known PD-L1 antagonist with a proven bioactivity BMS1166. Subsequently, we modified both compounds to allow 18F labeling that could be used for PET imaging. Radiolabeling, which is used in drug development and diagnosis, was applied to investigate the properties of those ligands and test them against tissue sections with diverse expression levels of PD-L1. We confirmed biological activity toward hPD-L1 for this inhibitor, comparable with BMS1166, while holding enhanced pharmacological properties.

Original language	English
Pages (from-to)	9577-9591
Number of pages	15
Journal	Journal of Medicinal Chemistry
Volume	66
Issue number	14
DOIs	https://doi.org/10.1021/acs.jmedchem.3c00254
Publication status	Published - 27-Jul-2023

Keywords

Immune Checkpoint Inhibitors
B7-H1 Antigen

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Design, Synthesis, and Biological EvaluationFinal publisher's version, 6.72 MBLicence: CC BY

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Ważyńska, M. A., Butera, R., Requesens, M., Plat, A., Zarganes-Tzitzikas, T., Neochoritis, C. G., Plewka, J., Skalniak, L., Kocik-Krol, J., Musielak, B., Magiera-Mularz, K., Rodriguez, I., Blok, S. N., de Bruyn, M., Nijman, H. W., Elsinga, P. H., Holak, T. A., & Dömling, A. (2023). Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors. Journal of Medicinal Chemistry, 66(14), 9577-9591. https://doi.org/10.1021/acs.jmedchem.3c00254

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abstract = "In search of a potent small molecular PD-L1 inhibitor, we designed and synthesized a compound based on a 2-hydroxy-4-phenylthiophene-3-carbonitrile moiety. Ligand's performance was tested in vitro and compared side-by-side with a known PD-L1 antagonist with a proven bioactivity BMS1166. Subsequently, we modified both compounds to allow 18F labeling that could be used for PET imaging. Radiolabeling, which is used in drug development and diagnosis, was applied to investigate the properties of those ligands and test them against tissue sections with diverse expression levels of PD-L1. We confirmed biological activity toward hPD-L1 for this inhibitor, comparable with BMS1166, while holding enhanced pharmacological properties. ",

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author = "Wa{\.z}y{\'n}ska, {Marta A} and Roberto Butera and Marta Requesens and Annechien Plat and Tryfon Zarganes-Tzitzikas and Neochoritis, {Constantinos G} and Jacek Plewka and Lukasz Skalniak and Justyna Kocik-Krol and Bogdan Musielak and Katarzyna Magiera-Mularz and Ismael Rodriguez and Blok, {Simon N} and {de Bruyn}, Marco and Nijman, {Hans W} and Elsinga, {Philip H} and Holak, {Tad A} and Alexander D{\"o}mling",

year = "2023",

month = jul,

day = "27",

doi = "10.1021/acs.jmedchem.3c00254",

language = "English",

volume = "66",

pages = "9577--9591",

journal = "Journal of Medicinal Chemistry",

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Ważyńska, MA, Butera, R, Requesens, M , Plat, A, Zarganes-Tzitzikas, T, Neochoritis, CG, Plewka, J, Skalniak, L, Kocik-Krol, J, Musielak, B, Magiera-Mularz, K, Rodriguez, I, Blok, SN, de Bruyn, M , Nijman, HW , Elsinga, PH, Holak, TA & Dömling, A 2023, 'Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors', Journal of Medicinal Chemistry, vol. 66, no. 14, pp. 9577-9591. https://doi.org/10.1021/acs.jmedchem.3c00254

Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors. / Ważyńska, Marta A; Butera, Roberto; Requesens, Marta et al.
In: Journal of Medicinal Chemistry, Vol. 66, No. 14, 27.07.2023, p. 9577-9591.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors

AU - Ważyńska, Marta A

AU - Butera, Roberto

AU - Requesens, Marta

AU - Plat, Annechien

AU - Zarganes-Tzitzikas, Tryfon

AU - Neochoritis, Constantinos G

AU - Plewka, Jacek

AU - Skalniak, Lukasz

AU - Kocik-Krol, Justyna

AU - Musielak, Bogdan

AU - Magiera-Mularz, Katarzyna

AU - Rodriguez, Ismael

AU - Blok, Simon N

AU - de Bruyn, Marco

AU - Nijman, Hans W

AU - Elsinga, Philip H

AU - Holak, Tad A

AU - Dömling, Alexander

PY - 2023/7/27

Y1 - 2023/7/27

N2 - In search of a potent small molecular PD-L1 inhibitor, we designed and synthesized a compound based on a 2-hydroxy-4-phenylthiophene-3-carbonitrile moiety. Ligand's performance was tested in vitro and compared side-by-side with a known PD-L1 antagonist with a proven bioactivity BMS1166. Subsequently, we modified both compounds to allow 18F labeling that could be used for PET imaging. Radiolabeling, which is used in drug development and diagnosis, was applied to investigate the properties of those ligands and test them against tissue sections with diverse expression levels of PD-L1. We confirmed biological activity toward hPD-L1 for this inhibitor, comparable with BMS1166, while holding enhanced pharmacological properties.

AB - In search of a potent small molecular PD-L1 inhibitor, we designed and synthesized a compound based on a 2-hydroxy-4-phenylthiophene-3-carbonitrile moiety. Ligand's performance was tested in vitro and compared side-by-side with a known PD-L1 antagonist with a proven bioactivity BMS1166. Subsequently, we modified both compounds to allow 18F labeling that could be used for PET imaging. Radiolabeling, which is used in drug development and diagnosis, was applied to investigate the properties of those ligands and test them against tissue sections with diverse expression levels of PD-L1. We confirmed biological activity toward hPD-L1 for this inhibitor, comparable with BMS1166, while holding enhanced pharmacological properties.

KW - Immune Checkpoint Inhibitors

KW - B7-H1 Antigen

U2 - 10.1021/acs.jmedchem.3c00254

DO - 10.1021/acs.jmedchem.3c00254

M3 - Article

C2 - 37450644

SN - 0022-2623

VL - 66

SP - 9577

EP - 9591

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 14

ER -

Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors

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