Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein–Protein Interaction

Abstract

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.

Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, ADMET, and Molecular Dynamics (MD) Simulation of Potential Inhibitors of PD-L1 from the Library of Marine Natural Products

“…In this study, the available PD-L1 information of its small molecule inhibitors was used to construct the structure-based pharmacophore model. Hence, the 7 pharmacophore models containing the feature set were generated (Table 1) [31][32][33][34][35]. Among the generated models, 6R3K composed of DHHHNP chemical characteristics with the highest selectivity score (16.25) was selected as the best model.…”

PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action

“…Most of this work features the SAR analysis of biphenyl-cored molecules discovered by Bristol Myers Squibb. Although some new ideas such as symmetric molecules [21,22], terphenyls [17,18], or indolines [41] were proposed, only a moderate improvement of the bioactivity of the molecules could be achieved. It seems that the structure optimization of small molecules relying only on protein-based assays, such as the HTRF, is insufficient since many compounds present IC 50 values close to the lower limit of determination, but without a clear translation to the biological activity in a more complex, cellular environment.…”

“…Additionally, the maximal activation levels achievable for the molecules are frequently lower than the levels achieved for antibodies, which is due to the limited water solubilities and cytotoxic effects observed for some molecules when used at higher concentrations (above c.a. 2 µM) [5,18,22]. Some other molecules were shown to be less toxic, with 50% cell growth inhibition values above 10-30 µM [12,19,20].…”

“…The numeric data are also presented in Table 1. The molecules represent biphenyls [3][4][5][12][13][14][15][16], terphenyls [17,18], biphenyls with a ring fusion [19], elongated biphenyls [20], symmetric biphenyls [21][22][23], and macrocyclic peptides [10,11,24,25]. 1.…”

Small Molecule Agents Targeting PD-1 Checkpoint Pathway for Cancer Immunotherapy: Mechanisms of Action and Other Considerations for Their Advanced Development

“…A number of reports are also emerging recently from the industry and academia using the privileged structure of biphenyl-containing compounds and their various derivatives to improvise the druggability of the molecules. This includes scaffold based on nicotinyl alcohol ether derivative ( 45 – 47 ), resorcinol dibenzyl ether ( 48 ), 4-phenylindoline derivatives ( 49 ), combining two privileged scaffolds such as biphenyl backbone structure and 2-amino-pyrimidine structure ( 50 ), biphenyl-4-carboxamide derivatives ( 51 ), incorporating taurine moieties ( 52 ), 1-methyl-1H-pyrazolo[4,3-b] pyridine derivatives ( 53 ), replacing the linker connecting aryl group and biaryl core with a novel amine linker ( 54 ), a series of novel biphenyl pyridines derivatives lacking linker ( 55 ), biphenyl methyl nitrophenyl core unit ( 56 ), and terphenyl scaffold derived from the rigidified biphenyl inspired structure ( 57 ). Representative structures of the compounds disclosed are presented in Figure 3 .…”