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

被引：8

作者：

Wazynska, Marta A. A. ^{[1
]}

Butera, Roberto ^{[2
]}

Requesens, Marta ^{[1
]}

Plat, Annechien ^{[1
]}

Zarganes-Tzitzikas, Tryfon ^{[3
]}

Neochoritis, Constantinos G. G. ^{[4
]}

Plewka, Jacek ^{[5
]}

Skalniak, Lukasz ^{[5
]}

Kocik-Krol, Justyna ^{[5
,6
]}

Musielak, Bogdan ^{[5
]}

Magiera-Mularz, Katarzyna ^{[5
]}

Rodriguez, Ismael ^{[5
,6
]}

Blok, Simon N. N. ^{[7
]}

de Bruyn, Marco ^{[1
]}

Nijman, Hans W. W. ^{[1
]}

Elsinga, Philip H. H. ^{[7
]}

Holak, Tad A. A. ^{[5
]}

Domling, Alexander ^{[2
,8
,9
]}

机构：

[1] Univ Groningen, Univ Med Ctr Groningen, Dept Obstet & Gynecol, NL-9713 GZ Groningen, Netherlands

[2] Univ Groningen, Dept Drug Design, NL-9713 AV Groningen, Netherlands

[3] Alzheimers Res UK Oxford Drug Discovery Inst, Ctr Med Discovery, Nuffield Dept Med, Oxford OX3 7FZ, England

[4] Univ Crete, Dept Chem, Iraklion 70013, Greece

[5] Jagiellonian Univ, Fac Chem, Dept Organ Chem, PL-30387 Krakow, Poland

[6] Jagiellonian Univ, Doctoral Sch Exact & Nat Sci, PL-30348 Krakow, Poland

[7] Univ Groningen, Univ Med Ctr Groningen, Dept Nucl Med & Mol Imaging, NL-9713 GZ Groningen, Netherlands

[8] Palacky Univ Olomouc, Inst Mol & Translat Med, Fac Med & Dent, Olomouc 77900, Czech Republic

[9] Palacky Univ Olomouc, Czech Adv Technol & Res Inst, Olomouc 77900, Czech Republic

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 14期

关键词：

PD-1/PD-L1; BLOCKADE; 1,4-THIENODIAZEPINE-2,5-DIONES; GEWALD;

D O I：

10.1021/acs.jmedchem.3c00254

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In search of a potent small molecular PD-L1 inhibitor,we designedand synthesized a compound based on a 2-hydroxy-4-phenylthiophene-3-carbonitrilemoiety. Ligand's performance was tested in vitro and comparedside-by-side with a known PD-L1 antagonist with a proven bioactivityBMS1166. Subsequently, we modified both compounds to allow F-18 labeling that could be used for PET imaging. Radiolabeling, whichis used in drug development and diagnosis, was applied to investigatethe properties of those ligands and test them against tissue sectionswith diverse expression levels of PD-L1. We confirmed biological activitytoward hPD-L1 for this inhibitor, comparable with BMS1166, while holdingenhanced pharmacological properties.

引用

页码：9577 / 9591

页数：15

共 42 条

[1] In Vitro Assessment of Putative PD-1/PD-L1 Inhibitors: Suggestions of an Alternative Mode of Action
Blevins, Derek J.
Hanley, Ronan
Bolduc, Trevor
Powell, David A.
Gignac, Michael
Walker, Kayleigh
Carr, Mark D.
Hof, Fraser
Wulff, Jeremy E.
[J]. ACS MEDICINAL CHEMISTRY LETTERS, 2019, 10 (08): : 1187 - 1192
[2] BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[3] Blockade of programmed death-1 Ligands on dendritic cells enhances T cell activation and cytokine production
Brown, JA
Dorfman, DM
Ma, FR
Sullivan, EL
Munoz, O
Wood, CR
Greenfield, EA
Freeman, GJ
[J]. JOURNAL OF IMMUNOLOGY, 2003, 170 (03) : 1257 - 1266
[4] Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists
Butera, Roberto
Wazynska, Marta
Magiera-Mularz, Katarzyna
Plewka, Jacek
Musielak, Bogdan
Surmiak, Ewa
Sala, Dominik
Kitel, Radoslaw
de Bruyn, Marco
Nijman, Hans W.
Elsinga, Philip H.
Holak, Tad A.
Domling, Alexander
[J]. ACS MEDICINAL CHEMISTRY LETTERS, 2021, 12 (05): : 768 - 773
[5] Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export
Chen, Fang-Fang
Li, Zheng
Ma, Dawei
Yu, Qiang
[J]. ONCOIMMUNOLOGY, 2020, 9 (01):
[6] Computation of octanol-water partition coefficients by guiding an additive model with knowledge
Cheng, Tiejun
Zhao, Yuan
Li, Xun
Lin, Fu
Xu, Yong
Zhang, Xinglong
Li, Yan
Wang, Renxiao
Lai, Luhua
[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2007, 47 (06) : 2140 - 2148
[7] Chupak LS, 2015, PubChem, Patent No. [2015034820A1, 2015034820]
[8] European Medicines Agency, 2022, EMEAHC003985
[9] farmacotherapeutischkompas.nl, OPDIVO NIVOLUMAB PRI
[10] Comprehensive in vitro characterization of PD-L1 small molecule inhibitors
Ganesan, Aravindhan
Ahmed, Marawan
Okoye, Isobel
Arutyunova, Elena
Babu, Dinesh
Turnbull, William L.
Kundu, Joydeb Kumar
Shields, Justin
Agopsowicz, Katharine Cheryl
Xu, Lai
Tabana, Yasser
Srivastava, Nutan
Zhang, Guangzhi
Moon, Tae Chul
Belovodskiy, Alexandr
Hena, Mostofa
Kandadai, Appan Srinivas
Hosseini, Seyedeh N. Argess
Hitt, Mary
Walker, John
Smylie, Michael
West, Frederick G.
Siraki, Arno G.
Lemieux, M. Joanne
Elahi, Shokrollah
Nieman, James A.
Tyrrell, D. Lorne
Houghton, Michael
Barakat, Khaled
[J]. SCIENTIFIC REPORTS, 2019, 9 (1)

← 1 2 3 4 5 →