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In recent years, PD-1 immune checkpoint inhibitors based on monoclonal antibodies have revolutionized cancer therapy, but there still exist unresolved issues, such as the high cost, the relatively low response rates, and so on, compared with small-molecule drugs. Herein a type of pyrrole-imidazole (Py-Im) polyamide as a small-molecule DNA binder was designed and synthesized, which could competitively bind to the same double-stranded DNA stretch in the PD-L1 promoter region as the STAT3 binding site and thus downregulate PD-L1 expression. It was demonstrated that the Py-Im polyamides directly caused apoptosis in tumor cells and retarded cell migration in the absence of T cells through inhibiting the Akt/caspase-3 pathway. Also, in a coculture system, they enhanced the T-cell-mediated killing of tumor cells by the reversal of immune escape. Because such polyamides induced antitumor effects via both immune and nonimmune pathways, they could be further developed as promising PD-L1 gene-targeting antitumor drugs.

A series of new naphthalimide derivatives, benzothiophenonaphthalimides (7a-7g, 8a-8g), were designed and synthesized, of which compounds 8a-8g are hydrochloride salts of corresponding compounds 7a-7g. All compounds presented different anti-tumor activities for tumor cells tested by the CCK-8 assay. In particular, compound 7c displayed the strongest anti-tumor activity with an IC

In our work, 19 novel 4,5-diazafluorene derivatives (11a-d, 12a-d, 13a-d, 14a-c, 15c, 16a-c) bearing a 1,3-disubstituted pyrazol/thioxothiazolidinone or thioxothiazolidinone-oxadiazole moieties were designed, synthesized, preliminarily explored for their antitumor activities and in vitro mechanism. All compounds showed different values of antiproliferative activity against A549, AGS, HepG2 and MCF-7 cell lines through CCK-8. Especially, the compound 14c exhibited the strongest activity and best selectivity against A549 cells with an IC50 1.13 μM and an SI value of 7.01 relative to MRC-5 cells, which was better than cisplatin (SI = 1.80) as a positive control. Experimental results at extracellular level demonstrated that compounds 14a-c could strongly interact with the G-quadruplex(es) formed in a 26 nt telomeric G-rich DNA, in particular, the 14c exhibits quite strong binding affinity with an association equilibrium constant (KA) of 7.04(±0.16) × 107 M−1 and more than 1000-fold specificity to G4-DNA over ds-DNA and Mut-DNA at the compound/G4-DNA ratio of 1:1. Further trap assay ascertained that compounds 14a-c owned strong inhibitory ability of telomerase activity in A549 cells, suggesting that these compounds have great possibility to target telomeric G-quadruplexes and consequently indirectly inhibit the telomerase activity. In addition, it is worthy of note that the remarkable inhibitory effects of 14a-c on the mobility of tested cancer cells were observed by wound healing assays. Furthermore, molecular docking and UV–Vis spectral results unclose the rationale for the interaction of compounds with such G-quadruplex(es). These results indicate that the growth and metastasis inhibition of cancer cells mediated by these 4,5-diazafluorene derivatives possibly result from their interaction with telomeric G-quadruplexes, suggesting that 4,5-diazafluorene derivatives, especially 14c, possess potential as anticancer drugs.

In this study, we designed and synthesized a series of 3-(4-((5-((2-methylbiphenyl-3-yl) methoxy)-2-(piperazin-1-ylmethyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)benzonitrile derivatives and examined the effect of the compounds on the interaction between PD-1 and PD-L1. Among the newly synthesized compounds, compound 7 exhibited the most potent inhibitory activity for PD-1/PD-L1 binding, with an IC50 value being 8.52 μM, through homogeneous time-resolved fluorescence (HTRF) assay. Docking studies indicated that compound 7 can very well interact with PD-L1 dimerization like BMS-202 as a positive control, consistent with the results of the HTRF assay. Compound 7 is thus a promising candidate for further optimization as an inhibitor of the PD-1/PD-L1 signaling pathway.

Pyrrole-imidazole polyamide (PIP) can specifically bind in the B-DNA minor groove that has been used in several biological applications, such as anti-cancer activity, gene expression and translation control, and visualization of complex genomic areas. c-kit is a family member of the Tyrosine Kinase (RTK) type III receptor and plays a vital role in tumor growth, proliferation, differentiation, and cell apoptosis; however, its mutations and overexpression induce tumor dysfunction. Here, we designed and synthesized five matched PIPs that can recognize and bind to the DNA sequence in the oncogene c-kit promoter region, and evaluated their anti-cancer activity. The RTCA assay findings revealed that the PIPs would prevent the proliferation of cancer cells A549 and SGC-7901. EMSA assay showed that the PIPs were actively interacting with the c-kit gene target DNA. RT-PCR and Western blot assays have an effect on expression levels of the c-kit gene in the presence of PIPs. Flow cytometry and wound-healing assays showed that PIPs 4, 5 would cause apoptosis of cancer cells and inhibit the migration of cells, respectively. Overall findings indicate that PIP 5 has a relatively significant intracellular and extracellular impact on the target, contributing to migration and proliferation reduction, and cancer cell apoptosis. In addition, PIP has a certain ability to evolve into c-kit gene-targeting drugs.