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In recent years, several monoclonal antibodies (mAbs) targeting PD-L1 have been licensed by the FDA for use in the treatment of cancer, demonstrating the effectiveness of blocking immune checkpoints, particularly the PD-1/PD-L1 pathway. Although mAb-based therapies have made great strides, they still have their limitations, and new small-molecule or PROTAC-molecule inhibitors that can block the PD-1/PD-L1 axis are desperately needed. Therefore, it is crucial to translate initial in vitro discoveries into appropriate in vivo animal models when creating PD-L1-blocking therapies. Due to their widespread availability and low experimental expenses, classical immunocompetent mice are appealing for research purposes. However, it is yet unclear whether the mouse (m) PD-L1 interaction with human (h) PD-1 in vivo would produce a functional immunological checkpoint. In this review, we summarize the in vitro and in vivo experimental studies of small molecules and PROTAC molecules, particularly the distinctions between m PD-L1 as a target and h PD-L1 as a target. [Display omitted] • It is yet unclear if the mPD-L1/hPD-1 interaction would produce a Functional immunological checkpoint in vivo. • We outlined the most variation among mPD-L1 and hPD-L1 when used as targets. • We summarized PROTACs-based molecules that inhibit cancer by targeting PD-L1. [ABSTRACT FROM AUTHOR]

Nepetalactol, an iridoid with four chiral carbons, is a crucial component of aphid sex pheromones that have been employed with great success to control the insect-related diseases. Despite of agricultural usage as end products, iridoids are fundamental biosynthetic intermediates for pharmaceutically important monoterpenoid indole alkaloids such as camptothecin (CAM) and vinca alkaloids. Herein we characterized 10-hydroxygeraniol oxidoreductase (10HGO) and iridoid synthase (IS) from Camptotheca acuminata , a CAM-producing plant, and reported their application in biological preparation of nepetalactol. Ca10HGO and CaIS were respectively cloned from C. acuminata , overexpressed in Escherichia coli , and purified to homogeneity. Ca10HGO catalyzes the oxidation of 10-hydroxygeraniol into 10-oxogeranial, in which NADP+ was reduced to NADPH. CaIS catalyzes nepetalactol formation from 10-oxogeranial using NADPH cofactor. The net outcome of the two reactions generate nepetalactol from 10-hydroxygeraniol efficiently, indicating NADP+ - NADPH recycling. Ca10HGO and CaIS were co-overexpressed in E. coli under optimized fermentation conditions to prepare cell-based catalysts that catalyze the conversion of 10-hydroxygeraniol into nepetalactol. The present work shows the enzymatic conversion of 10-hydroxygeraniol into nepetalactol involved in CAM biosynthesis. Co-overexpression of Ca10HGO and CaIS in E. coli is an alternative valuable cell-based biotransformation process with regenerating recycling of NADP+ - NADPH cofactors for nepetalactol preparation. • Ca10HGO and CaIS were cloned from camptothecin-producing plant Camptotheca acuminata. • Ca10HGO and CaIS were expressed in Escherichia coli and functionally characterized. • In vitro combinatory assays of Ca10HGO and CaIS verified recycling of NADP+ - NADPH. • 10-Hydroxygeraniol was converted into nepetalactol by E. coli expressing Ca10HGO-IS. [ABSTRACT FROM AUTHOR]

PD-1 (Programmed cell death-1) is a receptor that inhibits the activation of T cells and is an important target for cancer immunotherapy. PD-1 expression stays high on antigen-specific T cells that have been stimulated for a long time, making them less responsive to stimuli. Consequently, there has been a recent surge in the number of researchers focusing on how the PD-1 axis delivers inhibitory signals to uncover new therapeutic targets. As an inhibitory signaling mechanism, the PD-1 axis controls immunological responses. Blocking the PD-1 axis has been shown to have long-lasting effects on various cancers, demonstrating the crucial role of PD-1 in blocking anti-tumor immunity. Despite this role, most patients do not respond to PD-1 monotherapy, and some have experienced adverse events. Many challenges remain regarding the PD-1 signaling axis to be addressed. In this review, we outline the most recent research and prospects of PD-1 signal inhibitors to enhance cervical cancer therapy. [Display omitted] • Discuss the small molecule inhibitors targeting the PD-1 signaling axis. • Outline the PD-1 signal inhibitors and their potential to improve cervical cancer therapy. • Drugs and drug candidates that target the PD-1 signaling axis have been shown. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the ability of compound 13d to induce autophagy and to promote apoptosis of tumor cells and its interaction mechanism. Using CCK-8 assay, transwell assay, fluorescence resonance energy transfer melting analysis (FRET), transmission electron microscopy, flow cytometry assay, immunofluorescence assay, Western blot analysis, and wound healing assay. The results indicated that compound 13d could induce autophagy and apoptosis of gastric cancer cells. Moreover, the findings of CCK-8 assay, colony formation, migration and invasion assay, and wound healing assay revealed that compound 13d would effectively inhibit cell proliferation, migration, and invasion. Its IC 50 value is about 2.4 μM against gastric cancer cells, which is similar to positive drug‑platinum. 13d specific induction of telomere G-quadruplex formation was proved in extracellular FRET melting assay, and indirectly affected telomerase activity. G-quadruplex formation promoted cell apoptosis and autophagy. Upon incorporating the autophagy inhibitors 3-MA and HCQ, the expression of the autophagy marker protein LC3 was then checked, suggesting that the compound 13d influences the autophagy flux. Furthermore, knocking down the autophagy-related gene Atg5 to reduce the level of autophagy enhances the anti-tumor activity and increases apoptotic cells' proportion. Mechanistic experiments have shown that blocking the Akt/m-TOR signal pathway plays a crucial role in autophagy and G-quadruplex induced telomere dysfunction. DNA damage is the leading cause of autophagy. Compound 13d combined with autophagy inhibitor can inhibit tumor cells more effectively. Our findings demonstrate that compound 13d as a telomeric G-quadruplex ligand induces Telomere dysfunction, DNA damage response, autophagy, and apoptosis in gastric cancer cells by blocking the Akt/m-TOR signaling pathway. [Display omitted] • This study aimed to evaluate the ability of a 1,10-phenanthroline derivative (13d) to kill gastric cells and its interaction mechanism. • The findings revealed that 13d would effectively inhibit cell proliferation, migration, and invasion. • 13d triggers cytoprotective autophagy by blocking the Akt/mTOR signal pathway in autophagy-dependent gastric cancer cells. [ABSTRACT FROM AUTHOR]

The outbreak of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, in December 2019, and its global dissemination became the coronavirus disease 2019 (COVID-19) pandemic declared by the World Health Organization (WHO) on 11 March 2020. In patients undergoing immunotherapy, the effect and path of viral infection remain uncertain. In addition, viral-infected mice and humans show T-cell exhaustion, which is identified after infection with SARS-CoV-2. Notably, they regain their T-cell competence and effectively prevent viral infection when treated with anti-PD-1 antibodies. Four clinical trials are officially open to evaluate anti-PD-1 antibody administration's effectiveness for cancer and non-cancer individuals influenced by COVID-19 based on these findings. The findings may demonstrate the hypothesis that a winning strategy to combat SARS-CoV-2 infection could be the restoration of exhausted T-cells. In this review, we outline the potential protective function of the anti-PD-1 blockade against SARS-CoV-2 infection with the aim to develop SARS-CoV-2 therapy. [Display omitted] • The effect and course of viral infection in patients receiving immunotherapy are still unknown. • Anti-PD-1 antibody treatment is currently being evaluated in four clinical trials for cancer and non-cancer patients that have been affected by COVID-19. • We outline the potential protective role of the anti-PD-1 blockade against SARS-CoV-2 infection with the aim to develop SARS-CoV-2 treatment. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade has displayed substantial anti-tumor resistance in a variety of forms of cancer, but the fundamental regulation role remains unclear, and several questions continue to be addressed. PD-1/PD-L1 has been recognized as an anti-cancer drug target for several years, and through targeting the PD-1/PD-L1 signaling pathway, many monoclonal antibodies have thus far produced promising results in cancer therapy. The discovery of small-molecule inhibitors focused on the PD-1/PD-L1 signaling pathway is steadily reviving over decades, owing to the intrinsic shortcomings of the antibodies. PD-1 function and its PD-L1 or PD-L2 ligands are essential for the activation, proliferation, and cytotoxic secretion of T-cells in cancer to degenerate anti-tumor immune response. The axis PD-1/PD-L1 is important for the immune escape of cancer which has an immense impact on cancer treatment. In this review, we summarize the function of PD-1 and PD-L1 in cancer and aiming to enhance cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

G-quadruplexes (G4) are secondary four-stranded DNA helical structures consisting of guanine-rich nucleic acids, which can be formed in the promoter regions of several genes under proper conditions. Several cancer cells have been shown to emerge from genomic changes in the expression of crucial growth-regulating genes that allow cells to develop and begin to propagate in an undifferentiated state. Recent attempts have focused on producing treatments targeted at particular protein products of genes that are abnormally expressed. Many of the proteins found are hard to target and considered undruggable due to structural challenges, protein overexpression, or mutations that affect treatment resistance. The utilization of small molecules that stabilize secondary DNA structures existing in several possible oncogenes' promoters and modulate their transcription is a new strategy that avoids some of these problems. In this review, we outline the function of G-quadruplex stabilization in cancer by small-molecules with the aim to improve cancer therapy. [Display omitted] • G-quadruplexes are involved in several cellular functions, such as replicating DNA, gene expression, telomere protection, and apoptosis. • The critical future challenge is to explain the complexities of how G4 formation is regulated. • We outline the role of G-quadruplex stabilization by small-molecules in cancer-related genes with the aim to improve cancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Drug repurposing, depicting patented medicines as an effective technique to develop drugs. • Drug repurposing, compared to de novo drug discovery, could shorten the duration and reduce costs. • Remdesivir and Favipiravir, despite having side effects, were more promising drugs for SARS-CoV-2 infection. • Considering the unparalleled morbidity and deaths associated with the COVID-19 pandemic, a vaccine against COVID-19 is urgently needed. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causal factor of the coronavirus disease 2019 (COVID-19). Drug repurposing, portraying patented drugs as a successful drug development technique, could shorten the period and minimize costs relative to de novo drug exploration. Recently several drugs have been used as anti-SARS-CoV-2 such as Remdesivir, Favipiravir, Hydroxychloroquine, Azithromycin, Lopinavir/Ritonavir, Nafamostat mesylate and so on. Despite such efforts, there is currently no successful broad-spectrum antiviral countermeasures to combat SARS-CoV-2 or possibly potential CoVs pandemic. Therefore it is desperately important to recognize and test widely efficient, reliable anti-CoV therapies now and in the future. Remdesivir and Favipiravir were more promising despite having side effects; it had prominent efficacy and efficiency while still not yet approved as the official anti-viral drug for SARS CoV-2. In this review, we summarizes the current drug and vaccine discovery status against SARS-CoV-2, predicting that these efforts will help create effective drugs and vaccines for SARS-CoV-2. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the impact of four synthesized benzoxazinone derivatives as screening drugs on c-Myc-overexpressed cancer cells (H7402, HeLa, SK-RC-42, SGC7901, and A549) and to explore their interaction mechanisms in detail. Using morphological analysis, real-time cytotoxicity analysis, wound healing assay, reverse transcription PCR, electrophoretic mobility shift assay, and circular dichroism spectroscopy techniques. Results revealed that these four compounds could inhibit proliferation of SK-RC-42, SGC7901, and A549 cells in five cancer cell lines to varying degrees and significantly hinder migration. More importantly, the RT-PCR assay showed that the compounds could surprisingly downregulate the expression of c-Myc mRNA in a dose-dependent manner in the five cancer cells, which may be one of the causes of cancer cell proliferation in vitro inhibition. Further EMSA assays demonstrated that at the molecular level of DNA, four compounds can induce the formation of G-quadruplexes (G4-DNAs) in the c-Myc gene promoter. In addition, the CD result of compound 1 clearly indicates that it specifically induces a c-Myc GC-rich 36mer double-stranded DNA in the c-Myc promoter to form a G-quadruplex hybrid configuration. In conclusion, the compounds studied could dose-dependently inhibit the growth and migration of the cancer cells being investigated. This is positively associated with the reduction of overexpression of the c-Myc gene, which may be significantly regulated by the association of compounds with the G-quadruplexes produced in the c-Myc gene promoter region. We conclude that three compounds merit further study, particularly against non-small-cell lung cancer, as leading compounds of anticancer drugs. Unlabelled Image • The derivatives of benzoxazinone are small molecules with anti-platelet aggregation, anti-viral and anticancer effects. • We investigated the impact of four synthesized derivatives of benzoxazinone as screening drugs. • We evaluated their effect on the proliferation, apoptosis and migration of H7402, HeLa, SK-RC-42, SGC7901 and A549 tumor cells that overexpress c-Myc, and their interaction mechanisms preliminary. • These four compounds have been shown to inhibit concentration-dependent tumor cell proliferation and growth. [ABSTRACT FROM AUTHOR]

A series of novel 2-arylmethoxy-4-(2-fluoromethyl-biphenyl-3-ylmethoxy) benzylamine derivatives was designed, synthesized, and evaluated for their antitumor effects as PD-1/PD-L1 inhibitors both in vitro and in vivo. Firstly, the ability of these compounds to block the PD-1/PD-L1 immune checkpoint was assessed using the homogeneous time-resolved fluorescence (HTRF) assay. Two of the compounds can strongly block the PD-1/PD-L1 interaction, with IC 50 values of less than 10 nM, notably, compound HD10 exhibited significant clinical potential by inhibiting the PD-1/PD-L1 interaction with an IC 50 value of 3.1 nM. Further microscale thermophoresis (MST) analysis demonstrated that HD10 had strong interaction with PD-L1 protein. Co-crystal structure (2.7 Å) analysis of HD10 in complex with the PD-L1 protein revealed a strong affinity between the compound and the target PD-L1 dimer. This provides a solid theoretical basis for further in vitro and in vivo studies. Next, a typical cell-based experiment demonstrated that HD10 could remarkably prevent the interaction of hPD-1 293 T cells from human recombinant PD-L1 protein, effectively restoring T cell function, and promoting IFN-γ secretion in a dose-dependent manner. Moreover, HD10 was effective in suppressing tumor growth (TGI = 57.31 %) in a PD-1/PD-L1 humanized mouse model without obvious toxicity. Flow cytometry, qPCR, and immunohistochemistry data suggested that HD10 inhibits tumor growth by activating the immune system in vivo. Based on these results, it seems likely that HD10 is a promising clinical candidate that should be further investigated. [Display omitted] • Novel 2-fluoromethyl-biphenyl containing benzylamine derivatives were synthesized. • HD10 exhibited significant clinical potential as a PD-1/PD-L1 inhibitor. • Co-crystal structure (2.7 Å) of HD10 with the PD-L1 protein revealed their strong interaction. • HD10 showed tumor growth inhibition (TGI = 57.31 %) in a humanized mouse model without obvious toxicity. [ABSTRACT FROM AUTHOR]

[Display omitted] • New A56 -based PROTACs target-degrading PD-L1 have been designed and synthesized. • Compounds 9i and 9j induce the internalization and degradation of PD-L1 in HCC-827 cells. • Compounds 9i and 9j degrade of PD-L1 through dual means of lysosome and proteasome. • The compounds have good anti-tumor activity by activating immunity in vivo. Currently, antibody drugs targeting programmed cell death ligand 1 (PD-L1) have achieved promising results in cancer treatment, while the development of small-molecule drugs lags behind. In this study, we designed and synthesized a series of PD-L1-degrading agents based on the PROTAC design principle, utilizing the PD-L1 inhibitor A56. Through systematic screening of ligands and linkers and investigating the structure–activity relationship of the degraders, we identified two highly active compounds, 9i and 9j. These compounds enhance levels of CD4+, CD8+, granzyme B, and perforin, demonstrating significant in vivo antitumor effects with a tumor growth inhibition (TGI) of up to 57.35 %. Both compounds facilitate the internalization of PD-L1 from the cell surface and promote its degradation through proteasomal and lysosomal pathways, while also maintaining inhibition of the PD-1/PD-L1 interaction. In summary, our findings provide a novel strategy and mechanism for developing biphenyl-based PROTAC antitumor drugs targeting and degrading PD-L1. [ABSTRACT FROM AUTHOR]

PD-L1 is an important immune checkpoint protein that can bind to T cells' PD-1 receptor, thereby promoting immune escape from tumors. In recent years, many researchers have developed strategies to degrade PD-L1 to improve the effect of immunotherapy. The study of degrading PD-L1 provides new opportunities for immunotherapy. Here, we mainly summarize and review the current active molecules and mechanisms that mediate the degradation of immature and mature PD-L1 during the post-translational modification stages, involving PD-L1 phosphorylation, glycosylation, palmitoylation, ubiquitination, and the autophagy-lysosomal process. This review expects that by degrading PD-L1 protein, we will not only gain a better understanding of oncogenic mechanisms involving tumor PD-L1 protein but also provide a new way to improve immunotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Background/Aim Probiotics have been suggested as prophylactic measure in colon carcinogenesis. This study aimed at determining the potential prophylactic activity of Lactobacillus rhamnosus GG CGMCC 1.2134 (LGG) strain on colorectal carcinogenesis via measuring its effect on Nuclear factor kappa B (NFκB) inflammatory pathway and apoptosis. Materials and methods 64 Sprague Dawley rats were grouped into four as follows; Group 1 (Healthy control), Group 2 (LGG), Group 3 (cancer control Dimethyl hydrazine (DMH)) and Group 4 (LGG + DMH). LGG was administered orally to LGG and LGG + DMH groups. Colon carcinogenesis was chemically induced in LGG + DMH and DMH groups by weekly injection of 40 mg/kg DMH. Animals were sacrificed after 25 weeks of experiment and tumor characteristics assessed. The change in expression of NFκB-p65, COX-2, TNFα, Bcl-2, Bax, iNOS, VEGFα, β-catenin, Casp3 and p53 were evaluated by western blotting and qRT-PCR. Results LGG treatment significantly reduced tumor incidence, multiplicity and volume in LGG + DMH treatment group compared to DMH cancer control group. Also, LGG treatment reduced the expression of β-catenin and the inflammatory proteins NFκB-p65, COX-2 and TNFα; the anti-apoptotic protein Bcl-2, but increased the expression of the pro-apoptotic proteins Bax, casp3 and p53 compared with DMH group. Conclusion LGG have a potential protection effect against colon carcinogenesis; inducing apoptosis and ameliorating inflammation, and may hold a promise as bio-therapeutic dietary agent. [ABSTRACT FROM AUTHOR]

In this study, a series of novel naphthalimide-benzotriazole conjugates (1a – 3c) based on 1, 8-naphthalimide as a core skeleton, aiming at G-quadruplexes, were designed and synthesized, and their anti-cancer activity and mechanism were studied. Using the CCK-8 assay, FRET melting, EMSA, CD, and molecular docking, intracellular assays, western blotting, immunofluorescence, and flow cytometry. By the CCK-8 assay, it was found that the compound, 2-(3-(piperazin-1-yl)propyl)-6-(1H-benzo [d][1,2,3]triazol-1-yl)-1 H -benzo[ de ]isoquinoline-1,3(2 H)-dione (3a), has better activity against A549 cells. Through extracellular assays, including FRET melting, EMSA, CD, and molecular docking, results showed that 3a selectively interacted with BCL2 G-quadruplex(es). Further studies by intracellular assays, including western blotting, immunofluorescence, flow cytometry, etc., verified that 3a mediated the death of A549 cells by two pathways: inhibition of the expression of the BCL2 gene, causing tumor cell apoptosis, and promotion of genetic instability, causing autophagy. This study suggests that the type of compounds, in particular, 3a , may be a potential molecule to explore for BCL2 G-quadruplex-targeted drugs against lung cancer. Our findings demonstrate that compound 3a as a BCL2 G-quadruplex ligand induces DNA damage, autophagy, and apoptosis in A549 cells. This study provides us with a type of lead compound as an anti-tumor drug. [Display omitted] • 9 novel naphthalimide-benzotriazole conjugates were synthesized. • 3a showed the strongest inhibitory activity against A549 cells. • 3a stabilized Bcl-2 G-quadruplexes and induced apoptosis and autophagic cell death. [ABSTRACT FROM AUTHOR]

[Display omitted] 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 50 value of 0.59 ± 0.08 μM and the best selectivity for HepG2 cells. At the same time, it was observed that 7c could induce HepG2 cell apoptosis, hinder cancer cell migration and arrest the cell cycle at the G2/M phase. Further mechanism studies revealed that 7c selectively induced a G-rich HRCC DNA sequence in the mitochondria to form a G-quadruplex structure (G4) and stabilized it, which mediated the decrease in mitochondrial membrane potential and the production of reactive oxygen species, causing mitochondrial dysfunction. Finally, this led to proliferative inhibition and apoptosis of cancer cells and protective autophagy by promoting the expression of p-Erk1/2. The in vivo experimental results indicated that the compound 8c as a salt of 7c showed significant in vivo anti-tumor efficacy in the HepG2-xenograft mouse model with a tumor growth inhibition rate of 51.4% at a dose of 15 mg/kg. These results suggest that 7c possesses a different anti-tumor mechanism from the previous main reported mechanism of naphthalimide derivatives, which targets the nucleus. In brief, 7c has good anti-tumor activity in vitro and in vivo and may act as a leading compound in development of drugs against liver cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • 7-O-substituted pyridyl-4-methyl naphthopyrone derivatives were synthesized. • The mechanism for the formation of naphthopyrone derivatives was proposed. • Compound 7 possess stronger in vitro cytotoxicity for A549 cells. • Compounds with linear alkyl groups displayed strong anti-proliferative ability. Coumarins are naturally evolving molecules that have a wide variety of activities. In medical chemistry and chemical biology, their structural and physicochemical properties make them a suitable scaffold. Herein, we designed and synthesized novel coumarin analogues-7-O-substituted pyridyl-4-methyl naphthopyrone derivatives and initially evaluated their anti-cancer activity. RTCA profiling reveals that compounds 6 , 7 and 8 , in particular 7 , possess stronger in vitro cytotoxicity for A549 cells. All synthesized compounds have been characterized by 1H NMR spectra, elemental analysis, and mass spectrometry. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effect of previously synthesized 4,5-diazafluorene derivative (14c) on γδ T cell-mediated cytotoxicity against renal cell carcinoma (RCC). A real-time cell analyzer monitored cell proliferation, and Cell Counting Kit-8 determined cell viability. A reverse transcription-polymerase chain reaction analyzed gene expression, and protein expression was determined by cellular immunofluorescence analysis and Western blot. The compound 14c induced the expression of immunomodulatory molecules, such as natural killer group 2, member D ligands (NKG2DLs), fibroblast-associated (Fas) death receptor, and tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAILRs) in RCC. In addition, 14c induced DNA damage responses in RCC. Blocking DNA damage by KU-55933 reduced the effect of γδ T cells on 14c-treated RCC, suggesting that DNA damage responses were involved in the augmentation of γδ T cell-mediated cytotoxicity. Treating 786-O cells with a nitrogen-containing bisphosphonate prodrug further enhanced the anti-tumor effect of γδ T cell plus 14c combination treatment. The present evidence indicates that 14c induced DNA damage responses in RCC and augmented γδ T cell-mediated cytotoxicity primarily through NKG2D/NKG2DLs pathways, suggesting potential cancer immunotherapy for harnessing γδ T cells and small compounds that induce DNA damage responses. Unlabelled Image • Previously we designed and synthesized a 4,5-diazafluorene derivative (14c). • We investigated the impact of previously synthesized 4,5-diazafluorene derivative (14c) on γδ T cell-mediated cytotoxicity against renal cell carcinoma (RCC). • This study would shed light on new strategies in the development of anti-tumor immunotherapies. [ABSTRACT FROM AUTHOR]

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. Image 1 • 5 novel pyrrole-imidazole polyamides (PIPs) targeting c-kit gene were synthesized. • PIP 5 presented most potent inhibitory effect and apoptotic ability on SGC-7901 with an IC50 value of 2.96 ± 0.08 μM. • PIPs could target-downregulate the expression level of c-kit gene, leading to the apoptosis of SGC-7901 and A549 cells. [ABSTRACT FROM AUTHOR]