Discovery of a novel, potent and selective small‐molecule inhibitor of PD‐1/PD‐L1 interaction with robust in vivo anti‐tumour efficacy

Abstract

Background and purpose PD‐1/PD‐L1 antibodies have achieved great success in clinical treatment. However, monoclonal antibody drugs also have challenges, such as high manufacturing costs, poor diffusion, low oral bioavailability and limited penetration into tumour tissue. The development of small‐molecule inhibitors of PD‐1/PD‐L1 interaction represents a promising perspective to overcome the above challenges in cancer immunotherapy. Experimental approach We explored structural activity relationships and used biochemical assays to generate a lead compound (ZE132). CD8+ T‐cells killing assay and Ifng expression assay were used to verify the in vitro cellular activity of ZE132. Off‐target study was performed to verify the selectivity. Syngeneic mouse models were used to verify the in vivo activity of ZE132 in tumour immune microenvironment (TIME). We also performed pharmacokinetics profiling in mice and The Cancer Genome Atlas database analysis. Key results ZE132 can effectively inhibit the PD‐1/PD‐L1 interactions in vitro, and it has a potent affinity to PD‐L1. ZE132 shows robust anti‐tumour effects in vivo, better than anti‐PD‐1 antibody. In the analysis of TIME, we found that ZE132 treatment promotes cytotoxic T‐cell tumour infiltration and induces IL‐2 expression. In addition, ZE132 elicits strong inhibitory effects on the mRNA expression of TGF‐β, which may serve as a potential biomarker to predict responsiveness to PD‐1/PD‐L1 immunotherapies. Conclusion and implications We identified a new lead compound ZE132 targeting PD‐1/PD‐L1 interactions, not only showing favourable drug‐like properties in vitro and in vivo but also showing the advantage of overcoming the barrier of TIME compared to anti‐PD‐1 antibody.

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

“…The residue was further purified using a silica gel column to afford the desired products. (26). White solid, HPLC: rt: 13.313 min, purity: 99.5%, yield: 46%.…”

“…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. Although many of these compounds showed high inhibitory potency against PD-1/PD-L1 interactions both in vitro and in vivo, none of them have entered clinical studies.…”

Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells

“…MDM4 and MDM2 binding affinities were tested in corresponding fluorescence polarization (FP) assays 55 with RG7388 and a well-known MDM2 inhibitor Nutlin-3a 11 as positive controls (Figure 3). Hydrogenation of the CN group of RG7388 led to compound 13, which reduced MDM2/4 binding affinities to 6.5 and 9932 nM, in terms of K i values, respectively.…”

“…4-((2R,3S,4S,5S)-4-(4-Chlorophenyl)-3-(3-chlorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic Acid(55). Method C: 55d (24 mg, 0.04 mmol), 4-(bromomethyl)pyridine hydrobromide (20 mg, 0.08 mmol), K 2 CO 3(22 mg, 0.16 mmol), and LiOH•H 2 O (8 mg, 0.2 mmol) were used.…”

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 .…”