Inhibition of PD-1/PD-L1 protein-protein interaction

Novel PD-1/PD-L1 protein-protein interaction inhibitors were designed and evaluated for activity and mechanism using XRD2 structural data.

(Ref: Basu E. et al, JMedChem, 62(15), 7520-7263 (2019))

The programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint serves to mediate peripheral immune tolerance and to protect against excessive inflammation and autoimmunity. Several tumors evoke immunosuppressive mechanisms to evade immune system attacks. Cancer immunotherapies targeting the PD1/PD-L1 immune checkpoint pathway have reversed the immunosuppression defensive approaches, resulting in remarkable clinical effects. A series of C2-symmetric inhibitors was designed and evaluated for inhibitory activity against the PD-1/PD-L1 protein-protein interaction (IC50’s in the nM range). X-ray structural studies provided structural insights into the interaction, using XRD2 data.

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Design, synthesis, evaluation and structural studies of C2-symmetric small molecule inhibitors of the programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) protein-protein interaction,
Subhadwip Basu, Jeffrey Yang, Bin Xu, Katarzyna Magiera-Mularz, Lukasz Skalniak, Bogdan Musielak, Vladyslav Kholodovych, Tadeuz A. Holak and Longqin Hu
Journal of Medicinal Chemistry 2019 62(15), 7520-7263, doi: 10.1021/acs.jmedchem.9b00795, PDB: 6RPG
Last Updated on Sunday, 29 September 2019 13:58