ABSTRACT
The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound 14d, featuring an 8a-N-acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3, but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N-acylhydrazone to enhance drug-like properties.
Subject(s)
Aldehydes , Anti-Obesity Agents , Hydrazones , Obesity , Animals , Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/therapeutic use , Anti-Obesity Agents/chemistry , Hydrazones/pharmacology , Hydrazones/chemistry , Hydrazones/chemical synthesis , Hydrazones/pharmacokinetics , Hydrazones/therapeutic use , Mice , Structure-Activity Relationship , Aldehydes/chemistry , Male , Obesity/drug therapy , Mice, Inbred C57BL , Diet, High-Fat/adverse effects , Humans , Mice, Obese , Molecular StructureABSTRACT
Mitochondrial DNA (mtDNA) G-quadruplexes (G4s) have important regulatory roles in energy metabolism, yet their specific functions and underlying regulatory mechanisms have not been delineated. Using a chemical-genetic screening strategy, we demonstrated that the JAK/STAT3 pathway is the primary regulatory mechanism governing mtDNA G4 dynamics in hypoxic cancer cells. Further proteomic analysis showed that activation of the JAK/STAT3 pathway facilitates the translocation of RelA, a member of the NF-κB family, to the mitochondria, where RelA binds to mtDNA G4s and promotes their folding, resulting in increased mtDNA instability, inhibited mtDNA transcription, and subsequent mitochondrial dysfunction. This binding event disrupts the equilibrium of energy metabolism, catalyzing a metabolic shift favoring glycolysis. Collectively, the results provide insights into a strategy employed by cancer cells to adapt to hypoxia through metabolic reprogramming.
ABSTRACT
WRN helicase is a critical protein involved in maintaining genomic stability, utilizing ATP hydrolysis to dissolve DNA secondary structures. It has been identified as a promising synthetic lethal target for microsatellite instable (MSI) cancers. However, few WRN helicase inhibitors have been discovered, and their potential binding sites remain unexplored. In this study, we analyzed potential binding sites for WRN inhibitors and focused on the ATP-binding site for screening new inhibitors. Through molecular dynamics-enhanced virtual screening, we identified two compounds, h6 and h15, which effectively inhibited WRN's helicase and ATPase activity in vitro. Importantly, these compounds selectively targeted WRN's ATPase activity, setting them apart from other non-homologous proteins with ATPase activity. In comparison to the homologous protein BLM, h6 exhibits some degree of selectivity towards WRN. We also investigated the binding mode of these compounds to WRN's ATP-binding sites. These findings offer a promising strategy for discovering new WRN inhibitors and present two novel scaffolds, which might be potential for the development of MSI cancer treatment.
Subject(s)
Adenosine Triphosphate , Antineoplastic Agents , Enzyme Inhibitors , Molecular Dynamics Simulation , Werner Syndrome Helicase , Adenosine Triphosphate/chemistry , Binding Sites , Werner Syndrome Helicase/antagonists & inhibitors , Werner Syndrome Helicase/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Drug Screening Assays, Antitumor , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Microsatellite Instability/drug effects , Neoplasms/genetics , HumansABSTRACT
c-MYC is a hallmark of various cancers, playing a critical role in promoting tumorigenesis. The formation of G-quadruplex (G4) in the c-MYC promoter region significantly suppresses its expression. Therefore, developing small-molecule ligands to stabilize c-MYC G4 formation and subsequentially suppress c-MYC expression is an attractive topic for c-MYC-driven cancer therapy. However, achieving selective ligands for c-MYC G4 poses challenges. In this study, we developed a series of triazole-modified quinazoline (TMQ) derivatives as potential c-MYC G4 ligands and c-MYC transcription inhibitors from 4-anilinoquinazoline lead 7a using click chemistry. Importantly, the c-MYC G4 stabilizing ability and antiproliferation activity were well correlated among these new derivatives, particularly in the c-MYC highly expressed colorectal cancer cell line HCT116. Among them, compound A6 exhibited good selectivity in stabilizing c-MYC G4 and in suppressing c-MYC transcription better than 7a. This compound induced G4 formation, selectively inhibited G4-related c-MYC transcription and suppressed the progression of HCT116 cells. These findings identify a new c-MYC transcription inhibitor and provide new insights for optimizing c-MYC G4-targeting ligands.
Subject(s)
Aniline Compounds , Antineoplastic Agents , G-Quadruplexes , Click Chemistry , Proto-Oncogene Proteins c-myc , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Quinazolines/pharmacology , Quinazolines/chemistry , Triazoles/pharmacology , LigandsABSTRACT
Hyperactivated KRAS mutations fuel tumorigenesis and represent attractive targets for cancer treatment. While covalent inhibitors have shown clinical benefits against the KRASG12C mutant, advancements for non-G12C mutants remain limited, highlighting the urgent demand for pan-KRAS inhibitors. RNA G-quadruplexes (rG4s) in the 5'-untranslated region of KRAS mRNA can regulate KRAS translation, making them promising targets for pan-KRAS inhibitor development. Herein, we designed and synthesized 50 novel coumarin-quinolinium derivatives, leveraging our previously developed rG4-specific ligand, QUMA-1. Notably, several compounds exhibited potent antiproliferative activity against cancer cells as pan-KRAS translation inhibitors. Among them, 15a displayed exceptional capability in stabilizing KRAS rG4s, suppressing KRAS translation, and consequently modulating MAPK and PI3K-AKT pathways. 15a induced cell cycle arrest, prompted apoptosis in KRAS-driven cancer cells, and effectively inhibited tumor growth in a KRAS mutant xenograft model. These findings underscore the potential of 15a as a pan-KRAS translation inhibitor, offering a novel and promising approach to target various KRAS-driven cancers.
Subject(s)
G-Quadruplexes , Proto-Oncogene Proteins p21(ras) , Humans , Cell Line, Tumor , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Protein Synthesis Inhibitors , MutationABSTRACT
Mitochondrion-lysosome interactions have garnered significant attention in recent research. Numerous studies have shown that mitochondrion-lysosome interactions, including mitochondrion-lysosome contact (MLC) and mitophagy, are involved in various biological processes and pathological conditions. Single fluorescent probes are termed a pivotal chemical tool in unraveling the intricate spatiotemporal interorganelle interplay in live cells. However, current chemical tools are insufficient to deeply understand mitochondrion-lysosome dynamic interactions and related diseases, Moreover, the rational design of mitochondrion-lysosome dual-targeting fluorescent probes is intractable. Herein, we designed and synthesized a pH-sensitive fluorescent probe called INSA, which could simultaneously light up mitochondria (red emission) and lysosomes (green emission) for their internal pH differences. Employing INSA, we successfully recorded long-term dynamic interactions between lysosomes and mitochondria. More importantly, the increasing mitochondrion-lysosome interactions in ferroptotic cells were also revealed by INSA. Further, we observed pH variations in mitochondria and lysosomes during ferroptosis for the first time. In brief, this work not only introduced a pH-sensitive fluorescent probe INSA for the disclosure of the mitochondrion-lysosome dynamic interplays but also pioneered the visualization of the organellar pH alternation in a specific disease model.
Subject(s)
Fluorescent Dyes , Lysosomes , Humans , Fluorescent Dyes/metabolism , Lysosomes/metabolism , Mitochondria , HeLa Cells , Hydrogen-Ion ConcentrationABSTRACT
G-quadruplexes (G4) are special nucleic acid structures with diverse conformational polymorphisms. Selective targeting of G-quadruplex conformations and regulating their biological functions provide promising therapeutic intervention. Despite the large repertoire of G4-binding tools, only a limited number of them can specifically target a particular G4 conformation. Here, we introduce a novel method, G4-SELEX-Seq and report the development of the first L-RNA aptamer, L-Apt12-6, with high binding selectivity to parallel G4 over other nucleic acid structures. Using parallel dG4 c-kit 1 as an example, we demonstrate the strong binding affinity between L-Apt12-6 and c-kit 1 dG4 in vitro and in cells, and notably report the applications of L-Apt12-6 in controlling DNA replication and gene expression. Our results suggest that L-Apt12-6 is a valuable tool for targeting parallel G-quadruplex conformation and regulating G4-mediated biological processes. Furthermore, G4-SELEX-Seq can be used as a general platform for G4-targeting L-RNA aptamers selection and should be applicable to other nucleic acid structures.
Subject(s)
Aptamers, Nucleotide , G-Quadruplexes , Nucleic Acids , Aptamers, Nucleotide/chemistryABSTRACT
Obesity, a global pandemic posing a growing threat to human health, necessitates the development of effective and safe anti-obesity agents. Our previous studies highlighted the lipid-lowering effects of indolylquinazoline Bouchardatine and its derivatives. In this study, we employed scaffold hopping and simplification strategies to design and synthesize two new series derivatives by modifying the D ring. Extensive discussions have been conducted regarding the structure-activity relationship between lipid-lowering activity and the new compounds. These discussions have resulted in the discovery of 2-pyrimidinylindole derivatives as a promising scaffold for anti-obesity treatment. The new 2-pyrimidinylindole derivatives exhibited comparable lipid-lowering activity to the previously reported indolylquinazoline derivatives, including SYSU-3d and R17, with reduced toxicity. The most potent compound, 5a, demonstrated a larger therapeutic index, improved aqueous solubility and oral bioavailability compared to the previous lead compounds. In vivo evaluation indicated that 5a effectively reduced lipid accumulation in adipose tissue, improved glucose tolerance, and mitigated insulin resistance and liver function damage caused by a high-fat and high-cholesterol diet. Mechanism studies indicated that 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. Overall, our study has identified a highly active compound 5a, and provided the basis for further development of 2-pyrimidinylindole as a promising scaffold for obesity treatment.
Subject(s)
Anti-Obesity Agents , Hypercholesterolemia , Humans , Lipid Metabolism , Anti-Obesity Agents/pharmacology , Biological Availability , Obesity/drug therapy , LipidsABSTRACT
Metabolic reprogramming is a crucial hallmark of tumorigenesis. Modulating the reprogrammed energy metabolism is an attractive anticancer therapeutic strategy. We previously found a natural product, bouchardatine, modulated aerobic metabolism and inhibited proliferation in the colorectal cancer cell (CRC). Herein, we designed and synthesized a new series of bouchardatine derivatives to discover more potential modulators. We applied the dual-parametric high-content screening (HCS) to evaluate their AMP-activated protein kinase (AMPK) modulation and CRC proliferation inhibition effect simultaneously. And we found their antiproliferation activities were highly correlated to AMPK activation. Among them, 18a was identified with nanomole-level antiproliferation activities against several CRCs. Interestingly, the evaluation found that 18a selectively upregulated oxidative phosphorylation (OXPHOS) and inhibited proliferation by modulating energy metabolism. Additionally, this compound effectively inhibited the RKO xenograft growth along with AMPK activation. In conclusion, our study identified 18a as a promising candidate for CRC treatment and suggested a novel anti-CRC strategy by AMPK activating and OXPHOS upregulating.
Subject(s)
AMP-Activated Protein Kinases , Colorectal Neoplasms , Humans , AMP-Activated Protein Kinases/metabolism , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Indole Alkaloids/pharmacology , Energy Metabolism , Cell Proliferation , Cell Line, TumorABSTRACT
Helicases are crucial enzymes in DNA and RNA metabolism and function by unwinding particular nucleic acid structures. However, most convenient and high-throughput helicase assays are limited to the typical duplex DNA. Herein, we developed an immunosorbent assay to monitor the Werner syndrome (WRN) helicase unwinding a wide range of DNA structures, such as a replication fork, a bubble, Holliday junction, G-quadruplex and hairpin. This assay could sensitively detect the unwinding of DNA structures with detection limits around 0.1 nM, and accurately monitor the substrate-specificity of WRN with a comparatively less time-consuming and high throughput process. Remarkably, we have established that this new assay was compatible in evaluating helicase inhibitors and revealed that the inhibitory effect was substrate-dependent, suggesting that diverse substrate structures other than duplex structures should be considered in discovering new inhibitors. Our study provided a foundational example for using this new assay as a powerful tool to study helicase functions and discover potent inhibitors.
Subject(s)
RecQ Helicases , Werner Syndrome , Humans , RecQ Helicases/genetics , RecQ Helicases/metabolism , Immunosorbents , DNA Replication , Werner Syndrome Helicase/genetics , Werner Syndrome Helicase/metabolism , Exodeoxyribonucleases/metabolism , DNA/chemistry , Werner Syndrome/geneticsABSTRACT
Developing c-MYC transcription inhibitors that target the G-quadruplex has generated significant interest; however, few compounds have demonstrated specificity for c-MYC G-quadruplex and cancer cells. In this study, we designed and synthesized a series of benzoazole derivatives as potential G-quadruplex ligand-based c-MYC transcription inhibitors. Surprisingly, benzoselenazole derivatives, which are rarely reported as G-quadruplex ligands, demonstrated greater c-MYC G-quadruplex selectivity and cancer cell specificity compared to their benzothiazole and benzoxazole analogues. The most promising compound, benzoselenazole m-Se3, selectively inhibited c-MYC transcription by specifically stabilizing the c-MYC G-quadruplex. This led to selective inhibition of hepatoma cell growth and proliferation by affecting the MYC target gene network, as well as effective tumor growth inhibition in hepatoma xenografts. Collectively, our study demonstrates that m-Se3 holds significant promise as a potent and selective inhibitor of c-MYC transcription for cancer treatment. Furthermore, our findings inspire the development of novel selenium-containing heterocyclic compounds as c-MYC G-quadruplex-specific ligands and transcription inhibitors.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Ligands , Genes, myc , Cell ProliferationABSTRACT
Mutations in NRAS promote tumorigenesis and drug resistance. As this protein is often considered an undruggable target, it is urgent to develop novel strategies to suppress NRAS for anticancer therapy. Recent reports indicated that a G-quadruplex (G4) structure formed in the untranslated region of NRAS mRNA can downregulate NRAS translation, suggesting a potential NRAS suppression strategy. Here, we developed a novel cell-based method for large-scale screening of NRAS G4 ligand using the G-quadruplex-triggered fluorogenic hybridization probe and successfully identified the clinically used agent Octenidine as a potent NRAS repressor. This compound suppressed NRAS translation, blocked the MAPK and PI3K-AKT signaling, and caused concomitant cell cycle arrest, apoptosis, and autophagy. It exhibited better antiproliferation effects over clinical antimelanoma agents and could inhibit the growth of NRAS-mutant melanoma in a xenograft mouse model. Our results suggest that Octenidine may be a prominent anti-NRAS-mutant melanoma agent and represent a new NRAS-mutant melanoma therapy option.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Animals , Mice , Phosphatidylinositol 3-Kinases/metabolism , GTP Phosphohydrolases/genetics , GTP Phosphohydrolases/metabolism , Cell Line, Tumor , Melanoma/drug therapy , Melanoma/genetics , Melanoma/metabolism , Mutation , Membrane Proteins/genetics , Membrane Proteins/metabolismABSTRACT
Mitochondria have a crucial role in regulating energy metabolism and their dysfunction has been linked to tumorigenesis. Cancer diagnosis and intervention have a great interest in the development of new agents that target biomolecules within mitochondria. However, monitoring and modulating mitochondria RNA (mtRNA), an essential component in mitochondria, in cells is challenging due to limited functional research and the absence of targeting agents. In this study, we designed and synthesized a fluorescent quinolinium derivative, QUCO-1, which actively lit up with mtRNA in both normal and cancer cells in vitro. Additionally, we evaluated the function of QUCO-1 as an mtRNA ligand and found that it effectively induced severe mitochondrial dysfunction and OXPHOS inhibition in RKO colorectal cancer cells. Treatment with QUCO-1 resulted in apoptosis, cell cycle blockage at the G2/M phase, and the effective inhibition of cell proliferation. Our findings suggest that QUCO-1 has great potential as a promising probe and therapeutic agent for mtRNA, with the potential for treating colorectal cancer.
Subject(s)
Colorectal Neoplasms , Mitochondria , Humans , RNA, Mitochondrial/metabolism , Mitochondria/metabolism , Cell Proliferation , Apoptosis , Fluorescent Dyes/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Cell Line, TumorABSTRACT
Inter-organelle interactions play a vital role in diverse biological processes. Thus, chemical tools are highly desirable for understanding the spatiotemporal dynamic interplay among organelles in live cells and in vivo. However, designing such tools is still a great challenge due to the lack of universal design strategies. To break this bottleneck, herein, a novel unimolecular platform integrating the twisted intramolecular charge transfer (TICT) and aggregation-induced emission (AIE) dual mechanisms was proposed. As a proof of concept, two organelles, lipid droplets (LDs) and mitochondria, were selected as models. Also, the first TICT-AIE integration molecule, BETA-1, was designed for simultaneous and dual-color imaging of LDs and mitochondria. BETA-1 can simultaneously target LDs and mitochondria due to its lipophilicity and cationic structure and emit cyan fluorescence in LDs and red fluorescence in mitochondria. Using BETA-1, for the first time, we obtained long-term tracking of dynamic LD-mitochondrion interactions and identified several impressive types of dynamic interactions between these two organelles. More importantly, the increase in LD-mitochondrion interactions during ferroptosis was revealed with BETA-1, suggesting that intervening in the LD-mitochondrion interactions may modulate this cell death. BETA-1 was also successfully applied for in vivo imaging of LD-mitochondrion interactions in C. elegans. This study not only provides an effective tool for uncovering LD-mitochondrion interactions and deciphering related biological processes but also sheds light on the design of new probes with an integrated TICT-AIE mechanism for imaging of inter-organelle interactions.
Subject(s)
Caenorhabditis elegans , Lipid Droplets , Animals , Lipid Droplets/chemistry , Lipid Droplets/metabolism , Mitochondria/metabolism , Diagnostic ImagingABSTRACT
The homologous recombination repair (HRR) pathway is critical for repairing double-strand breaks (DSB). Inhibition of the HRR pathway is usually considered a promising strategy for anticancer therapy. The Bloom's Syndrome Protein (BLM), a DNA helicase, is essential for promoting the HRR pathway. Previously, we discovered quinazolinone derivative 9h as a potential BLM inhibitor, which suppressed the proliferation of colorectal cancer (CRC) cell HCT116. Herein, a new series of quinazolinone derivatives with N3-substitution was designed and synthesized to improve the anticancer activity and explore the structure-activity relationship (SAR). After evaluating their BLM inhibitory activity, the SAR was discussed, leading to identifying compound 21 as a promising BLM inhibitor. 21 exhibited the potent BLM-dependent cytotoxicity against the CRC cells but weak against normal cells. Further evaluation revealed that 21 could disrupt the HRR level while inhibiting BLM located on the DSB site and trigger DNA damage in the CRC cells. This compound effectively suppressed the proliferation and invasion of CRC cells, along with cell cycle arrest and apoptosis. Consequently, 21 might be a promising candidate for treating CRC, and the BLM might be a new potential therapeutic target for CRC.
Subject(s)
Bloom Syndrome , Colorectal Neoplasms , Humans , Bloom Syndrome/genetics , Quinazolinones/pharmacology , DNA Repair , DNA Damage , Colorectal Neoplasms/drug therapyABSTRACT
Recent successes in construction of light-up RNA aptamers allowed fluorescence-based live-cell imaging of RNAs. In addition, light-up aptamers have been converted into signaling aptamers that enable fluorometric detection of small chemicals. To date, only a single target chemical has been detected at a time in cells. In this study, we selected cladogenetic orthogonal light-up aptamers that output three different colors from the RNA library having the same ligand binding core. Two of the three functioned in mammalian cells. These two aptamers, which fluoresce blue and green upon binding of cognate fluorogen, were converted into signaling aptamers. Using these signaling aptamers in combination with a previously described light-up aptamer with red fluorescence, we demonstrated simultaneous detection of multiple chemicals in living cells. The cladogenetic orthogonal light-up aptamers developed in this study and the simple strategy for rational designing of the signaling aptamers will provide innovative advances in the field of RNA-based bioimaging.
Subject(s)
Aptamers, Nucleotide , Fluorescent Dyes , Animals , Fluorescent Dyes/chemistry , RNA/chemistry , Aptamers, Nucleotide/chemistry , Fluorometry , Mammals/metabolismABSTRACT
RNA imaging is of great importance for understanding its complex spatiotemporal dynamics and cellular functions. Considerable effort has been devoted to the development of small-molecule fluorescent probes for RNA imaging. However, most of the reported studies have mainly focused on improving the photostability, permeability, long emission wavelength, and compatibility with live-cell imaging of RNA probes. Less attention has been paid to the selectivity and detection limit of this class of probes. Highly selective and sensitive RNA probes are still rarely available. In this study, a new set of styryl probes were designed and synthesized, with the aim of upgrading the detection limit and maintaining the selectivity of a lead probe QUID-1 for RNA. Among these newly synthesized compounds, QUID-2 was the most promising candidate. The limit of detection (LOD) value of QUID-2 for the RNA was up to 1.8 ng/mL in solution. This property was significantly improved in comparison with that of QUID-1. Further spectroscopy and cell imaging studies demonstrated the advantages of QUID-2 over a commercially available RNA staining probe, SYTO RNASelect, for highly selective and sensitive RNA imaging. In addition, QUID-2 exhibited excellent photostability and low cytotoxicity. Using QUID-2, the global dynamics of RNA were revealed in live cells. More importantly, QUID-2 was found to be potentially applicable for detecting RNA granules in live cells. Collectively, our work provides an ideal probe for RNA imaging. We anticipate that this powerful tool may create new opportunities to investigate the underlying roles of RNA and RNA granules in live cells.
Subject(s)
Fluorescent Dyes , RNA , Fluorescent Dyes/chemistry , RNA Probes , Molecular ImagingABSTRACT
RNA G-quadruplex (rG4) structures in the 5' untranslated region (5'UTR) play crucial roles in fundamental cellular processes. ADAR is an important enzyme that binds to double-strand RNA and accounts for the conversion of Adenosine to Inosine in RNA editing. However, so far there is no report on the formation and regulatory role of rG4 on ADAR expression. Here, we identify and characterize a thermostable rG4 structure within the 5'UTR of the ADAR1 mRNA and demonstrate its formation and inhibitory role on translation in reporter gene and native gene constructs. We reveal rG4-specific helicase DHX36 interacts with this rG4 in vitro and in cells under knockdown and knockout conditions by GTFH (G-quadruplex-triggered fluorogenic hybridization) probes and modulates translation in an rG4-dependent manner. Our results further substantiate the rG4 structure-DHX36 protein interaction in cells and highlight rG4 to be a key player in controlling ADAR1 translation.
Subject(s)
G-Quadruplexes , 5' Untranslated Regions , RNA, Messenger/metabolismABSTRACT
c-MYC is a key driver of tumorigenesis. Repressing the transcription of c-MYC by stabilizing the G-quadruplex (G4) structure with small molecules is a potential strategy for cancer therapy. Herein, we designed and synthesized 49 new derivatives by introducing carbohydrates to our previously developed c-MYC G4 ligand 1. Among these compounds, 19a coupled with a d-glucose 1,2-orthoester displayed better c-MYC G4 binding, stabilization, and protein binding disruption abilities than 1. Our further evaluation indicated that 19a blocked c-MYC transcription by targeting the promoter G4, leading to c-MYC-dependent cancer cell death in triple-negative breast cancer cell MDA-MB-231. Also, 19a significantly inhibited tumor growth in the MDA-MB-231 mouse xenograft model accompanied by c-MYC downregulation. Notably, the safety of 19a was dramatically improved compared to 1. Our findings indicated that 19a could become a promising anticancer candidate, which suggested that introducing carbohydrates to improve the G4-targeting and antitumor activity is a feasible option.
Subject(s)
Antineoplastic Agents , G-Quadruplexes , 14-alpha Demethylase Inhibitors , Animals , Antineoplastic Agents/chemistry , Carbohydrates , Glucose , Humans , Imidazoles , Ligands , Mice , Proto-Oncogene Proteins c-myc/metabolism , Sugars , Sweetening AgentsABSTRACT
The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (1). Among the new compounds, a6 with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and 1 in TNBC cells. Remarkably, a6 caused more G4-related DNA damage and G4-related differentially expressed genes, consistent with its effect on disrupting the cell cycle, invasion, and glycolysis. Furthermore, a6 significantly suppresses the proliferation of various TNBC cells and the MDA-MB-231 xenograft model without evident toxicity. Our study suggests a novel strategy for TNBC therapeutics through dual-targeting HDAC and G4.