Design, synthesis, and evaluation of new benzimidazole‏ ‏‎thiourea ‎derivatives as antitumor agents

Archiv der Pharmazie, Год журнала: 2023, Номер 356(11)

Опубликована: Авг. 21, 2023

Novel benzimidazole thiourea derivatives were designed and synthesized based on sorafenib as a lead compound. The moiety was traded by the pyridine ring to enhance hydrophobic interaction retain hydrogen bonding in hinge region, while lipophilic moieties with different bulkiness employed deep pocket for better interactions. Thiourea urea bioisostere also utilized. Substantial activity demonstrated against leukemia subpanel an vitro antitumor screening at NCI. In single-dose assay, compounds 7i, 7j, 7l had GI%) higher than most cell lines (GI% = 86.2%-137.1%), five-dose compound outperformed HL-60(TB) SR terms of GI50 , TGI, LC50 . Compound caused cycle arrest G0-G1 S phases line induced apoptosis via elevating Bax/Bcl-2 ratio increasing caspases 3, 7, 9 5.1-, 3.2-, 5.2-fold, respectively. Compounds inhibited vascular ‎endothelial growth factor receptor-2 (VEGFR-2), B-Raf(V600E) platelet-derived receptor ‎beta (PDGFR-β) enzymes IC50 range 0.063-0.44 μM. COMPARE analysis molecular docking study performed predict possible mechanism action binding mode,

Язык: Английский

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The landscape of novel strategies for acute myeloid leukemia treatment: Therapeutic trends, challenges, and future directions

Toxicology and Applied Pharmacology, Год журнала: 2023, Номер 473, С. 116585 - 116585

Опубликована: Июнь 9, 2023

Язык: Английский

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Dr Jekyll and Mr Hyde: From Two Branches of Immune Response to Three Types of Interferon Response

Опубликована: Окт. 12, 2023

Interferons were the original prototype cytokine system discovered in 20th-century research. As name implies, they originally thought to be synthesised and secreted between cells. Thanks technological advances, processes involved protein secretion can explained comparatively more clearly at both genetic biochemical levels. The discovery of interferon (IFN) occurred when research was still its infancy. Franklin Wilkins structure function deoxyribonucleic acid (DNA) same time as Crick Watson; however, Isaacs Lindemann, two scientists, described first IFN 1957. Mutations caused by inherent synthesis during infection well within regulation pathways affecting cell proliferation. This remains central host effects through receptor subunits defined 6 domains. Type II is key immune a variety cells, mainly natural killer (NK) T Single–stranded and/or double–stranded RNA/DNA viruses, bacterial infections (e.g., _Escherichia coli_) fungal _Aspergillus_), also affect regulation. Pathogenic proteins utilise intra/extracellular that sense foreign antigens like Toll–like Receptors (TLRs), affected mutations human cellular transduction pathways. Since third type 2003, phenotypes further characterised, questions remain about immunological mechanisms contributing innate adaptive system. Alterations I/II/III IFNs differentially beneficially alter homeostatic pathological disease, with I being cancer Therefore, considered here are overall molecular, regulatory context developments.

Язык: Английский

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An Update on Protein Kinases as Therapeutic Targets—Part II: Peptides as Allosteric Protein Kinase C Modulators Targeting Protein–Protein Interactions

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(24), С. 17504 - 17504

Опубликована: Дек. 15, 2023

Human protein kinases are highly-sought-after drug targets, historically harnessed for treating cancer, cardiovascular disease, and an increasing number of autoimmune inflammatory conditions. Most current treatments involve small molecule kinase inhibitors that interact orthosterically with the ATP-binding pocket. As a result, these compounds often poorly selective highly toxic. Part I this series reviews role PKC isoforms in various human diseases, featuring cancer as well translational examples modulation applied to health disease. In present II, we discuss alternative allosteric binding mechanisms targeting PKC, novel platforms, such modified peptides. A major goal is design modulators enhanced selectivity improved pharmacological properties. To end, use molecular docking analysis predict action inhibitor-kinase interactions can facilitate development next-generation modulators.

Язык: Английский

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Profiling Cellular Morphological Changes Induced by Dual‐targeting PROTACs of Aurora Kinase and RNA‐binding Protein YTHDF2

ChemBioChem, Год журнала: 2024, Номер unknown

Опубликована: Июнь 5, 2024

Proteolysis targeting chimeras (PROTACs) are new chemical modalities that degrade proteins of interest, including established kinase targets and emerging RNA-binding (RBPs). Whereas diverse sets biochemical, biophysical cellular assays available for the evaluation optimizations PROTACs in understanding involved ubiquitin-proteasome-mediated degradation mechanism structure-degradation relationship, a phenotypic method profiling morphological changes is rarely used. In this study, first, we reported only examples degrading mRNA-binding protein YTHDF2 via screening multikinase PROTACs. Second, dual kinase- RBP-targeting using unbiased cell painting assay (CPA). The CPA analysis revealed high biosimilarity with aurora cluster annotated inhibitors, which reflected association between signaling network. Broadly, results demonstrated can be straightforward powerful approach to evaluate Complementary existing assays, provided perspective characterizing at morphology.

Язык: Английский

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[Review] The Landscape of Interferons in Health and Disease

Опубликована: Июль 15, 2024

Interferons (IFNs) were the original prototype cytokine system discovered in 20th century research. As name interferon implies (derived from Latin interfere-on), these proteins have immunostimulatory, primarily antiviral and antitumour properties are synthesised secreted between cells. Due to technological advances, processes variable factors involved IFN regulation can be comparatively explained by expressed genes expressed. In this review, we provide a brief introduction background on history of We then an overview type I IFNs, associated cells, their receptors outline characteristics subtypes. distinguished three types immune higher mammals cellular signalling mechanisms IFNs together with IFN–inducible transmembrane (IFITM) during viral infection. Additionally, elucidated role diseases, as well II immunological disorders, infections deficiency followed Errors signal transduction activator transcription (STAT) protein pathway disease analysed. This paper concludes examination I/II/III since discovery timing synthesis within cell pathways, examining autoantibodies, interferons errors, finally closing current understanding immunotherapy cancer.

Язык: Английский

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In Vitro Assessment of Inhibitory Effects of Kinase Inhibitors on CYP2C9, 3A and 1A2: Prediction of Drug-Drug Interaction Risk with Warfarin and Direct Oral Anticoagulants

European Journal of Pharmaceutical Sciences, Год журнала: 2024, Номер 203, С. 106884 - 106884

Опубликована: Авг. 30, 2024

This study aimed to evaluate the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of kinase inhibitors with warfarin and direct oral anticoagulants (DOACs).

Язык: Английский

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Development of Novel 1,3,4‐Trisubstituted Pyrazole Derivatives Bearing Sulfonamide Moiety as Anticancer Agents Targeting JNK Kinases

ChemistrySelect, Год журнала: 2024, Номер 9(40)

Опубликована: Окт. 1, 2024

Abstract In the present work, a new set of N ‐(2‐((4‐(1,3‐diphenyl‐1 H ‐pyrazol‐4‐yl)pyridine sulfonamide derivatives was synthesized. Final target compounds were tested against JNK1 and JNK2 isoforms. Compounds 8f 8d showed highest activity over both JNK They submicromolar (IC 50 0.90 µM 0.96 µM, respectively). also excellent 0.62 1.07 Moreover, final HL‐60 K‐562 cell lines for assessing in vitro anticancer using sorafenib as positive control. Compound potency at IC values 6.21 7.43 respectively. Furthermore, 8e 8g exhibited strong effects on acute leukemia cancer with 13.83 10.02 respectively, well chronic line 12.65 9.51 to examine its effect cycle. Finally, molecular docking study conducted understand plausible binding modes most active within sites.

Язык: Английский

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Exploration of drug repurposing for Mpox outbreaks targeting gene signatures and host-pathogen interactions

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

Опубликована: Ноя. 27, 2024

Monkeypox (Mpox) is a growing public health concern, with complex interactions within host systems contributing to its impact. This study employs multi-omics approaches uncover therapeutic targets and potential drug repurposing opportunities better understand Mpox's molecular pathogenesis. We developed an in silico host-pathogen interaction (HPI) network applied weighted gene co-expression analysis (WGCNA) explore between Mpox proteins. Subtype-specific protein-protein networks were constructed, key modules from the HPI WGCNA integrated identify significant To predict upstream signaling pathways transcription factors, we used eXpression2Kinases ChIP-X Enrichment Analysis. The multi-Steiner trees method was compare our findings those FDA-approved antiviral drugs. Analysis of 55 differentially expressed genes infection revealed 11 kinases 15 factors as regulators. identified 16 targets, categorized into 8 proviral (ESR2, ERK1, ERK2, P38, JNK1, CDK4, GSK3B, STAT3) designated for inhibition, (IKKA, HDAC1, HIPK2, TF65, CSK21, ESR2, GSK3B) activation. Proviral are involved AKT, Wnt, STAT3 pathways, while impact AP-1, NF-κB, apoptosis, IFN pathways. Promising candidates identified, including kinase inhibitors, steroid hormone receptor agonists, notably Niclosamide. enhances understanding by identifying repurposable drugs, providing valuable framework developing new treatments.

Язык: Английский

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Acquired resistance to tyrosine kinase targeted therapy: mechanism and tackling strategies

Drug Resistance Updates, Год журнала: 2024, Номер 78, С. 101176 - 101176

Опубликована: Ноя. 28, 2024

Язык: Английский

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