- Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein-Protein Interaction
-
We describe a new class of potent PD-L1/PD-1 inhibitors based on a terphenyl scaffold that is derived from the rigidified biphenyl-inspired structure. Using in silico docking, we designed and then experimentally demonstrated the effectiveness of the terphenyl-based scaffolds in inhibiting PD-1/PD-L1 complex formation using various biophysical and biochemical techniques. We also present a high-resolution structure of the complex of PD-L1 with one of our most potent inhibitors to identify key PD-L1/inhibitor interactions at the molecular level. In addition, we show the efficacy of our most potent inhibitors in activating the antitumor response using primary human immune cells from healthy donors.
- Muszak, Damian,Surmiak, Ewa,Plewka, Jacek,Magiera-Mularz, Katarzyna,Kocik-Krol, Justyna,Musielak, Bogdan,Sala, Dominik,Kitel, Radoslaw,Stec, Malgorzata,Weglarczyk, Kazimierz,Siedlar, Maciej,D?mling, Alexander,Skalniak, Lukasz,Holak, Tad A.
-
-
Read Online
- HYDROXY FORMAMIDE DERIVATIVES AND THEIR USE
-
Disclosed are compounds having the formula: (I) wherein R1, R2 and R3 are as defined herein, and methods of making and using the same, including use as inhibitors of BMP1, TLL1 and/or TLL2 and in treatment of diseases associated with BMP1, TLL1 and/or TLL2 activity.
- -
-
Page/Page column 120
(2017/01/26)
-
- HYDROXY FORMAMIDE DERIVATIVES AND THEIR USE
-
Disclosed are compounds having the formula: wherein R1, R2 and R3 are as defined herein, and methods of making and using the same, including use as inhibitors of BMP1, TLL1 and/or TLL2 and in treatment of diseases associated with BMP1, TLL1 and/or TLL2 activity.
- -
-
Paragraph 0489; 0490
(2016/12/16)
-
- HYDROXY FORMAMIDE DERIVATIVES AND THEIR USE
-
Disclosed are compounds having the formula (I): wherein R1, R2 and R3 are as defined herein, and methods of making and using the same, including use as inhibitors of BMP1, TLL1 and/or TLL2 and in treatment of diseases associated with BMP1, TLL1 and/or TLL2 activity.
- -
-
Page/Page column 97
(2015/07/23)
-