Journal of Medicinal Chemistry p. 5857 - 5867 (2017)
Update date:2022-08-05
Topics:
Guzik, Katarzyna
Zak, Krzysztof M.
Grudnik, Przemyslaw
Magiera, Katarzyna
Musielak, Bogdan
T?rner, Ricarda
Skalniak, Lukasz
D?mling, Alexander
Dubin, Grzegorz
Holak, Tad A.
Blockade of the PD-1/PD-L1 immune checkpoint pathway with monoclonal antibodies has provided significant advances in cancer treatment. The antibody-based immunotherapies carry a number of disadvantages such as the high cost of the antibodies, their limited half-life, and immunogenicity. Development of small-molecule PD-1/PD-L1 inhibitors that could overcome these drawbacks is slow because of the incomplete structural information for this pathway. The first chemical PD-1/PD-L1 inhibitors have been recently disclosed by Bristol-Myers Squibb. Here we present NMR and X-ray characterization for the two classes of these inhibitors. The X-ray structures of the PD-L1/inhibitor complexes reveal one inhibitor molecule located at the center of the PD-L1 homodimer, filling a deep hydrophobic channel-like pocket between two PD-L1 molecules. Derivatives of (2-methyl-3-biphenylyl)methanol exhibit the structures capped on one side of the channel, whereas the compounds based on [3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methanol induce an enlarged interaction interface that results in the open "face-back" tunnel through the PD-L1 dimer.
View MoreAnqing World Chemical Co., Ltd.
Contact:+86-556-5800026
Address:Daguan Economic Development Zone of circular economy industrial park Anqing City Anhui province
Contact:86 311 85902108 / 85902109
Address:room 1001-1005 ,huanghe Road ,shijiazhuang ,China
website:http://www.joyochem.com
Contact:0531-82687558, 0531-82687326
Address:Factory Building 11, Jinan Comprehensive free trade zone, Shandong, China
Contact:86-310-8067016
Address:East Fuhua Road,Tiexi Chemical Industrial Estate,Hebei,China
Qingdao Kingway Pharmtech Co., Ltd.
Contact:86-532-87118899
Address:No. 88, Middle Haixi Road, Jiaonan City, Qingdao, China
Doi:10.1039/a900081j
(1999)Doi:10.1021/om980369l
(1998)Doi:10.1016/S0040-4039(98)01087-9
(1998)Doi:10.1021/jm981031w
(1998)Doi:10.1016/S0022-328X(98)00577-4
(1998)Doi:10.1021/jo981006y
(1998)