Structure–activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Фев. 11, 2024

Abstract The tetrasubstituted naphthalene diimide compound QN-302 binds to G-quadruplex (G4) DNA structures. It shows high potency in pancreatic ductal adenocarcinoma (PDAC) cells and inhibits the transcription of cancer-related genes these PDAC animal models. is currently Phase 1a clinical evaluation as an anticancer drug. A study structure–activity relationships two related analogues (CM03 SOP1247) reported here. These have been probed using comparisons transcriptional profiles from whole-genome RNA-seq analyses, together with molecular modelling dynamics simulations. Compounds CM03 SOP1247 differ by presence a methoxy substituent latter: compounds closely similar profiles. Whereas (with additional benzyl-pyrrolidine group), although also showing down-regulatory effects same pathways, has on distinct genes, for example hedgehog pathway. This distinctive pattern affected hypothesized contribute its superior compared SOP1247. Its enhanced ability stabilize G4 structures attributed fitting into filling most space groove hydrogen atom or group

Язык: Английский

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Targeting c-MYC G-Quadruplexes for Cancer Treatment with Small Molecules

Scientia Pharmaceutica, Год журнала: 2025, Номер 93(1), С. 6 - 6

Опубликована: Янв. 22, 2025

Novel therapies are required due to the rising cancer burden. Conventional chemotherapeutics tend be particularly toxic, but there is a promising alternative for oncogenes, such as c-MYC. Often overexpressed in many types, potential c-MYC oncogene seems essential development of cancer. Targeting protein directly was limited, these DNA structures composed guanine-rich sequences suppress transcription. This review discusses recent advances developing small compounds that selectively bind and stabilize G-quadruplexes (G4). These molecules have also shown promise inhibition signaling tumor growth, suggesting G-quadruplex targeting could therapeutic

Язык: Английский

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MYC and therapy resistance in cancer: risks and opportunities

Molecular Oncology, Год журнала: 2022, Номер 16(21), С. 3828 - 3854

Опубликована: Окт. 10, 2022

The MYC transcription factor, encoded by the c‐ proto‐oncogene, is activated growth‐promoting signals, and a key regulator of biosynthetic metabolic pathways driving cell growth proliferation. These same processes are deregulated in MYC‐driven tumors, where they become critical for cancer proliferation survival. As other oncogenic insults, overexpressed induces series cellular stresses (metabolic, oxidative, replicative, etc.) collectively known as stress, which impact not only on tumor progression, but also response to therapy, with profound, multifaceted consequences clinical outcome. On one hand, recent evidence uncovered widespread role therapy resistance multiple types, either standard chemotherapeutic or targeted regimens. Reciprocally, imparts molecular dependencies cells, thus giving rise cancer‐specific vulnerabilities that may be exploited obtain synthetic‐lethal interactions novel anticancer drugs. Here we will review current knowledge links between therapeutic responses, discuss possible strategies overcome through new, interventions.

Язык: Английский

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G-Quadruplexes in c-MYC Promoter as Targets for Cancer Therapy

Biomedicines, Год журнала: 2023, Номер 11(3), С. 969 - 969

Опубликована: Март 21, 2023

Cancer is a societal burden demanding innovative approaches. A major problem with the conventional chemotherapeutic agents their strong toxicity and other side effects due to poor selectivity. Uncontrolled proliferation of cancer cells mutations, deletions, or amplifications in genes (oncogenes) encoding for proteins that regulate cell growth division, such as transcription factors, example, c-MYC. The direct targeting c-MYC protein has been attempted but so far unsuccessfully, it lacks definite binding site modulators. Meanwhile, another approach explored since discovery G-quadruplex secondary DNA structures formed guanine-rich sequences promoter region can downregulate this oncogene. Here, we will overview achievements made last decades towards new class anticancer drugs G-quadruplexes cells.

Язык: Английский

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Structural insights and shedding light on preferential interactions of dietary flavonoids with G-quadruplex DNA structures: A new horizon

Heliyon, Год журнала: 2023, Номер 9(3), С. e13959 - e13959

Опубликована: Фев. 20, 2023

G-quadruplex, a structurally unique structure in nucleic acids present all throughout the human genome, has sparked great attention therapeutic investigations. Targeting G-quadruplex is new strategy for drug development. Flavonoids are found almost dietary plant-based beverages and food products; therefore, they ingested significant proportions through diet. Although synthetically developed molecules used vigorously but have various adverse effects. While on other hand, nature supplies chemically scaffolds form of distinct flavonoids that easily accessible, less poisonous, higher bioavailability. Because their pharmacological effectiveness minimal cytotoxicity, such low molecular weight compounds feasible alternatives to synthetic medicines. Therefore, from drug-development point view, investigation screening binding capabilities quadruplex-interactive small natural like expected be highly effective, with particular emphasis selectivity towards polymorphic structures. In this respect, quadruplexes scintillated research into potential interaction these flavonoids. The purpose review offer an up-to-date close-up look at varied goal providing newer perspectives construct novel agents next-generation disease managements.

Язык: Английский

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Deciphering Binding Potential of Naphthalimide–Coumarin Conjugate with c-MYC G-Quadruplex for Developing Anticancer Agents: A Spectroscopic and Molecular Modeling Approach

ACS Applied Bio Materials, Год журнала: 2025, Номер unknown

Опубликована: Янв. 28, 2025

It has been well accumulated that G-quadruplex (G4-DNA) great anticancer relevance, and various heterocyclic moieties have synthesized examined as potent G4-DNA binders with promising activity. Here, we a series of naphthalimide-triazole-coumarin conjugates by substituting amines further examine their activity against 60 human cancer cell lines at 10 μM. One five dose concentration results reveal low values MG-MID GI50 for compounds including 8a (3.18 μM), 8b (13.11 8e (7.68 μM) 8f (1.75 μM). Further apoptosis manifests all can induce in cells stabilizing the c-MYC promoter G-quadruplex. Therefore, G-quadruplex-mediated pathway may be responsible these naphthalimide-coumarin caused cells. multispectroscopic techniques are employed to evaluate binding molecules where four readily bind stabilize it high constant, leading inhibition Binding studies toward ct-DNA disclose do not interact ds-DNA thus selectively target exert All active greater affinity Human Serum Albumin (HSA) HSA constant 12 × 104 M-1 (8a), 13.0 (8b), 14.2 (8e), 16.3 (8f). Thus, killing derivatives feasibly occur due ability forming promoters unfold agents taken clinical trials.

Язык: Английский

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Selective Recognition of Oncogene Promoter C-Myc G-Quadruplex: Design, Synthesis, and In Vitro Evaluation of Naphthalimide and Imidazo[1,2-a]pyrazines for Their Anticancer Activity

ACS Applied Bio Materials, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

c-Myc is a transcription factor that overexpressed in most human cancers. Despite its challenging nature, we have developed series of naphthalimide-imidazopyrazine conjugates to target c-Myc. The library synthesized derivatives was tested for their anticancer activity against nine-panel cancer cell lines. Compound 8eb showed excellent cytotoxicity all the lines, with range growth inhibition from -98.79% 96.62% at single-dose concentration 10-5 M. Further, employed 5-dose assay same which efficacy varying concentrations an MG-MID GI50 value 2.61 μM. Biophysical studies were performed explore interaction Pu27 over ct-DNA, oncogene promotor Pu22, and telomere, binding constant 1.3 × 107 M-1. Additionally, experiments get insights into mechanism between promoter. A molecular docking study unveiled stacking compound G4 DNA through groove binding, where very few reports are available, favorable energy -9.2 kcal/mol. Moreover, pharmacokinetic HOMO-LUMO gap analysis underscored potency active candidate. compound's ability toward HSA also assessed, results suggested effective HSA, revealing potential easy delivery site. above findings these newly candidates potent offer promising avenue as stabilizers.

Язык: Английский

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Targeting the RNA G-Quadruplex and Protein Interactome for Antiviral Therapy

Journal of Medicinal Chemistry, Год журнала: 2022, Номер 65(15), С. 10161 - 10182

Опубликована: Июль 21, 2022

In recent years, G-quadruplexes (G4s), types of noncanonical four-stranded nucleic acid structures, have been identified in many viruses that threaten human health, such as HIV and Epstein–Barr virus. this context, G4 ligands were designed to target the among which some shown promising antiviral effects. Perspective, we first summarize diversified roles RNA G4s different viruses. Next, introduce small-molecule developed modulators highlight their applications studies. addition G4s, comprehensively review medical intervention G4-interacting proteins from both virus (N protein, viral-encoded helicases, severe acute respiratory syndrome-unique domain, nuclear antigen 1) host (heterogeneous ribonucleoproteins, zinc-finger cellular nucelic acid-binding nucleolin) by inhibitors an alternative way disturb normal functions G4s. Finally, discuss challenges opportunities G4-based therapy.

Язык: Английский

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Structurally diverse G-quadruplexes as the noncanonical nucleic acid drug target for live cell imaging and antibacterial study

Chemical Communications, Год журнала: 2022, Номер 59(11), С. 1415 - 1433

Опубликована: Дек. 22, 2022

The recent advances in G-quadruplex-selective ligands the fields of live cell imaging, chemical biology and therapeutic prospects against bacterial infections.

Язык: Английский

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Organometallic Pillarplexes That Bind DNA 4-Way Holliday Junctions and Forks

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(25), С. 13570 - 13580

Опубликована: Июнь 15, 2023

Holliday 4-way junctions are key to important biological DNA processes (insertion, recombination, and repair) dynamic structures that adopt either open or closed conformations, the conformation being biologically active form. Tetracationic metallo-supramolecular pillarplexes display aryl faces about a cylindrical core, an ideal structure interact with junction cavities. Combining experimental studies MD simulations, we show Au pillarplex can bind (Holliday) in their form, binding mode not accessed by synthetic agents before. Pillarplexes 3-way too, but large size leads them up expand junction, disrupting base pairing, which manifests increased hydrodynamic lower thermal stability. At high loading, they rearrange both into Y-shaped forks increase available junction-like sites. Isostructural Ag similar behavior solution This contrasts (but complements) of cylinders, prefer structures. The pillarplexes' ability creates exciting possibilities modulate switch such biology, as well nucleic acid nanostructures. In human cells, do reach nucleus, antiproliferative activity at levels those cisplatin. findings provide new roadmap for targeting higher-order using approach, expanding toolbox design bioactive binders organometallic chemistry.

Язык: Английский

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