Novel Biphenyl Pyridines as Potent Small-Molecule Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

Abstract

With the successful clinical application of anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies (mAb), targeting the PD-1/PD-L1 interaction has become a promising method for the discovery of cancer therapy. Due to the inherent limitations of antibodies, it is necessary to search for small-molecule inhibitors against the PD-1/PD-L1 axis. We report the design, synthesis, and evaluation in vitro and in vivo of a series of novel biphenyl pyridines as the inhibitors of PD-1/PD-L1. 2-(((2-Methoxy-6-(2-methyl-[1,1′-biphenyl]-3-yl)­pyridin-3-yl)­methyl)­amino)­ethan-1-ol (24) was found to inhibit the PD-1/PD-L1 interaction with an IC50 value of 3.8 ± 0.3 nM and enhance the killing activity of tumor cells by immune cells. Compound 24 displays great pharmacokinetics (oral bioavailability of 22%) and significant in vivo antitumor activity in a CT26 mouse model. Flow cytometry and immunohistochemistry data indicated that compound 24 activates the immune activity in tumors. These results suggest that compound 24 is a promising small-molecule inhibitor against the PD-1/PD-L1 axis and merits further development.

Design, Synthesis, and Pharmacological Evaluation of Biaryl-Containing PD-1/PD-L1 Interaction Inhibitors Bearing a Unique Difluoromethyleneoxy Linkage

“…As shown in Table , by incorporating the difluoromethyleneoxy motif as an unusual bioisosteric replacement of the methoxy linkage and retaining other structural components intact, compound 25 displayed an IC 50 of 31.87 nM against the PD-1/PD-L1 interaction, which is slightly more potent than reference compound 2 (IC 50 = 48.2 nM). A quick screening of a small set of alkylamino alcohols/acids widely used in the literature ,,− as the solvent interaction structural motif indicated that all the resulting compounds 26–28 retained high inhibitory activity against the PD-1/PD-L1 interaction, and compound 28 bearing a 2-amino-2-methylpropane-1,3-diol component showed more increased potency with an IC 50 value of 16.31 nM. Keeping the 2-amino-2-methylpropane-1,3-diol component intact and changing the substitution pattern of the central tetra-substituted phenyl ring from 3-methyl to the 4-chloro pattern led to compound 29 , showing a much improved potency with an IC 50 value of 5.93 nM.…”

“…In addition, optimization of the methoxy (−CH 2 O−) linker was conducted by two groups. Jiang’s group removed the linker, and Li’s group replaced methoxy with the methylamino (−CH 2 NH 2 −) group, yielding compounds 7 and 8 with IC 50 values of 3.8 and 12.0 nM, respectively. Meanwhile, compounds 9 and 10 with high PD-1/PD-Ll blocking activity (IC 50 : 12.5 and 9.1 nM, respectively) were reported by the Chen group through modifying the solvent–interaction region. , More recently, Zhu and co-workers disclosed compound 11 bearing a taurine moiety located in the solvent interaction region with an IC 50 value of 9.1 nM.…”

Biphenyl Ether Analogs Containing Pomalidomide as Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

“…Inspired by recent findings concerning the effect of pomalidomide on PD-L1 induction [ 25 ] and postulated activity of PD-L1-targeting PROTACs [ 26 , 27 ], we designed several PD-L1–linker–pomalidomide synthetic constructs based on our recently published PROTAC and PD-L1 work [ 24 , 28 ]. The syntheses of the proposed inhibitors are shown in Scheme 1 , Scheme 2 and Scheme 3 and comprise the known syntheses of the PD-L1 inhibitors BMS-1166 and BMS-202 [ 17 , 19 , 29 , 30 ], terphenyl [ 31 , 32 ] and imidazopyridines [ 24 ], which then were linked together with pomalidomide derivatives to form the desired chimeras. All the pomalidomide intermediates used in the synthesis were obtained according to the known protocols.…”

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 .…”