Identification of a Selective Anticancer Agent from a Collection of Complex-And-Diverse Compounds Synthesized from Stevioside

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Compounds constructed by distorting the ring systems of natural products serve as a ready source complex and diverse molecules, useful for variety applications. Herein is presented use diterpenoids steviol isosteviol starting points construction >50 new compounds through this complexity-to-diversity approach, featuring novel system distortions noteworthy thallium(III) nitrate (TTN)-mediated fusion. Evaluation collection identified SteviX4 potent selective anticancer compound, inducing cell death at low nanomolar concentrations against some cancer lines in culture, compared to micromolar activity others. induces ferroptotic susceptible lines, target identification experiments reveal acts an inhibitor glutathione peroxidase 4 (GPX4), critical protein that protects cells ferroptosis. In its induction death, displays enhanced line selectivity relative most known GPX4 inhibitors. was used dependency on vulnerability certain not tied any one type cancer, suggesting inhibition type-agnostic strategy. With high fraction sp3-hybridized carbons considerable potency, unique among inhibitors, serving outstanding probe compound basis further translational development.

Language: Английский

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Inhibition of Kinase Activity and In Vitro Downregulation of the Protein Kinases in Lung Cancer and Cervical Cancer Cell Lines and the Identified Known Anticancer Compounds of Ziziphus mucronata

Plants, Journal Year: 2025, Volume and Issue: 14(3), P. 395 - 395

Published: Jan. 28, 2025

Plants have long been used as sources of natural compounds with therapeutic benefits, providing molecules capable inhibiting multiple kinases. Many medicinal plants are recognized for their anticancer properties and may offer ways to mitigate the adverse effects conventional cancer treatments. In this study, potential Ziziphus mucronata methanol extract a kinase inhibitor was assessed using MTT assay, universal human phosphokinase antibody array, along GC-MS analysis volatile compounds. The assay revealed strong cytotoxicity in A549 cells, an IC50 31.25 µg/mL, while HeLa cells showed weaker 125 µg/mL. comparison, paclitaxel exhibited potent inhibitory on (IC50 µg/mL) moderate inhibition 65 µg/mL). Enzyme activity, measured by ADP production ADP-Glo indicated that inhibited protein activity both after 24 h treatment. Additionally, which includes 44 pre-spotted kinases, downregulated phosphorylated kinases cell lines. Some affected such TOR, Fyn, HcK, Fgr, STAT5b, PLC-γ1, p38α, ERK1/2, AMPKA, Akt1/2, GSK-3α/β, MSK1/2, CREB, RSK1/2/3, STAT5a critical regulators various cellular processes, including apoptosis, differentiation, proliferation. findings study suggest from Z. capacity regulate highlighting significant growth inhibitors cells.

Language: Английский

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Quinoline and quinolone carboxamides: A review of anticancer activity with detailed structure–activity relationship analysis

Molecular Diversity, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Language: Английский

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Editorial: Exploring novel approaches to small molecule kinase inhibitors in cancer treatment

Frontiers in Chemistry, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 3, 2025

The dysregulation of protein kinase activity plays a pivotal role in the pathogenesis several diseases, including cancer. Therefore, kinases have become some most important drug targets for antitumor therapy 21st century. Approximately 538 known are encoded by human genome and regulate biological cellular processes. success imatinib, first oral tyrosine inhibitor approved Federal Drug Administration (FDA) 2001 chronic myelogenous leukemia, promoted extensive use inhibitors (KIs) as antiproliferative agents (Cohen et al., 2021;Roskoski, 2024). To date, 84 small molecule KIs been FDA 180 drugs clinical trials worldwide. Notably, 70 FDAapproved used targeted cancer therapies (Roskoski, However, only approximately 20% kinome has so far, underscoring potential studying additional to uncover novel treatment options. Most clinically act blocking ATP binding site active (type I) or inactive II) kinases. Beyond these, four classes identified: type III IV inhibitors, which allosteric targeting sites adjacent distant from ATP-binding pocket, respectively; V bivalent compounds that interact with two distinct regions domain; VI, covalent (Li Despite their undoubted advantages, such reduced side effects compared traditional chemotherapy convenient administration, face significant limitations. Key challenges include emergence acquired resistance, occurrence undesired effects, suboptimal pharmacokinetic profiles. These represent unmet needs need be overcome Recently, degraders interactors emerged strategies (Yu 2021;Klein, 2023;Zerihun 2023). emerging approaches pave way new therapeutic overcoming drug-resistant mutations.Recent advances described this Research Topic, collected three research articles review, received China, Morocco, Egypt, Saudi Arabia [https://www.frontiersin.org/research-topics/63906/exploring-novel-approaches-to-smallmolecule-kinase-inhibitors-in-cancer-treatment]. In study, Mohamed al. (Mohamed 2024) reported design synthesis series quinazoline-4-one/1,2,4-oxadiazole hybrid derivatives. proved dual EGFR BRAF V600E IC50 values at nanomolar level. Further investigation revealed promising against mutant form T790M (15-10 nM) comparable reference compound Osimertinib (IC50 8 nM). putative interactions key amino acid residues within target proteins also investigated, thus confirming potentialities class compounds. Computational studies valuable tool identification candidates. Alsfouk (Alsfouk employed computer-assisted strategy identify CDK9 CYP3A4 using predictive QSAR model silico synthesis. Molecular docking stable non-covalent between designed both targets. particular, strong H-bond pi-alkyl were crucial compounds' affinity. dynamics simulations MM/PBSA analysis further validated targets, sowing seeds development innovative effective inhibitors. Similarly, Faris (Faris conducted computational JAK3 They 41 pyrazolo-pyrimidine derivatives bearing an acrylamide group capable Cys909 residue JAK3's site. Using docking, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis, molecular modeling, MM/GBSA (Molecular Mechanics Generalized Born Surface Area) free energy techniques, investigated these molecules investigated. While study focused on treating rheumatoid arthritis, critical maturation white blood cells, T lymphocytes, B natural killer makes it hematological malignancies (Uckun 2007;Liongue results could contribution anti-cancer agents.In Zhang (Zhang provided in-depth MET structure its non-small cell lung (NSCLS). gene is oncogenic driver NSCLC, representing NSCLC treatment. Several capmatinib, savolitinib, tepotinib, patients metastatic harbouring mutations. context, gave overview currently developed highlighted mechanisms resistance therapies. Each Topic reports different explore treatment, offering data scientific community.

Language: Английский

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Discovery of novel naphthalene-based diarylamides as pan-Raf kinase inhibitors with promising anti-melanoma activity: rational design, synthesis, in vitro and in silico screening

Archives of Pharmacal Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

Raf kinase enzymes are often dysregulated in melanoma. While sorafenib demonstrates strong activity against wild-type B-Raf, it fails to effectively inhibit the mutated form of B-Raf. In this study, served as a lead compound for development new derivatives designed enhance inhibitory across multiple isoforms (pan-Raf inhibitors). Novel naphthalene-based diarylamide were subsequently designed, synthesized, and evaluated their biological various melanoma A375 cell line. Among these, 9a, containing difluoromethoxy group, demonstrated B-RafWT, B-RafV600E, c-Raf. Additionally, induced G2/M phase arrest triggered dose-dependent apoptosis, suppressing both proliferation survival. Compound 9a also exhibited high selectivity with minimal off-target effects, underscoring its specificity therapeutic potential Raf-driven malignancies.

Language: Английский

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A Comprehensive Overview of Protacs Targeting Hsp90 and Their Client Proteins for Cancer Therapy

Published: Jan. 1, 2025

Language: Английский

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Identifying Sex Differences in Lung Adenocarcinoma Using Multi-Omics Integrative Protein Signaling Networks

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Abstract Lung adenocarcinoma (LUAD) exhibits differences between the sexes in incidence, prognosis, and therapy, suggesting underexplored molecular mechanisms. We conducted an integrative multi-omics analysis using Clinical Proteomic Tumor Analysis Consortium (CPTAC) The Cancer Genome Atlas (TCGA) datasets to contrast transcriptomes proteomes sexes. used TIGER analyze TCGA-LUAD expression data found sex-biased activity of transcription factors (TFs); we PTM-SEA with CPTAC-LUAD proteomics kinase activity. combined these construct a kinase-TF signaling network discovered druggable pathways linked cancer-related processes. also significant sex biases clinically relevant TFs kinases, including NR3C1, AR, AURKA. Using PRISM drug screening database, identified potential sex-specific drugs, such as glucocorticoid receptor agonists aurora inhibitors. Our findings emphasize importance considering methods discover personalized cancer therapies.

Language: Английский

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Encrypting Cancer&#8217;s Morse Code: The Synergistic Power of CD47-SIRP<i>&#945;</i> Blockade and Tyrosine Kinase Inhibition

International Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 16(02), P. 135 - 153

Published: Jan. 1, 2025

Language: Английский

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Advancing Therapeutic Drug Monitoring for Oral Targeted Anticancer Drugs: From Hospital‐Based Towards Home‐Sampling

Biomedical Chromatography, Journal Year: 2025, Volume and Issue: 39(5)

Published: March 14, 2025

ABSTRACT Home‐sampling for therapeutic drug monitoring (TDM) oral targeted anticancer drugs offers a promising alternative to traditional hospital‐based sampling methods, though it presents challenges. This review aims summarize the state‐of‐the‐art of home‐sampling methods TDM and evaluates analytical clinical validation A comprehensive search was conducted across Embase, Medline, Scopus. Eligible articles described and/or drugs. ASReview used process unique references identify relevant studies. Of 39 included articles, 32 detailed on experiments, while 27 covered experiments. Dried blood spot volumetric absorptive microsampling were primary methods. Key challenges ensuring robust sample collection, pretreatment, hematocrit effects, stability, which generally thoroughly investigated. Clinical yielded results most analytes, although external remains crucial confirming reliability. show implementation. Methods well‐studied may be clinically implemented immediately, others require further validation. Future research should address device‐specific assess patient feasibility facilitate routine use in practice.

Language: Английский

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Computational Development of Allosteric Peptide Inhibitors Targeting LIM Kinases as a Novel Therapeutic Intervention

Cell Biochemistry and Biophysics, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Language: Английский

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