Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review

Frontiers in Chemistry, Journal Year: 2022, Volume and Issue: 10

Published: April 14, 2022

Targeted therapy is a groundbreaking innovation for cancer treatment. Among the receptor tyrosine kinases, fibroblast growth factor receptors (FGFRs) garnered substantial attention as promising therapeutic targets due to their fundamental biological functions and frequently observed abnormality in tumors. In past 2 decades, several generations of FGFR kinase inhibitors have been developed. This review starts by introducing basis FGF/FGFR signaling. It then gives detailed description different types small-molecule according modes action, followed systematic overview small-molecule-based therapies modalities. ends with our perspectives development novel inhibitors.

Language: Английский

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Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 1

Journal of Agricultural and Food Chemistry, Journal Year: 2022, Volume and Issue: 70(36), P. 10942 - 10971

Published: June 8, 2022

Piperazine and homopiperazine are well-studied heterocycles in drug design that have found gainful application as scaffolds terminal elements for enhancing the aqueous solubility of a molecule. The optimization candidates incorporate these an effort to refine potency, selectivity, developability properties has stimulated evaluation wide range bioisosteres can offer advantage. In this review, we summarize piperazine almost exclusively been arena. While there ∼100 approved drugs ring, only single marketed agricultural product is built on heterocycle. As part discuss some potential reasons underlying relatively low level importance heterocycle agrochemicals highlight opportunities their use contemporary research programs.

Language: Английский

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Chemical proteomics reveals the target landscape of 1,000 kinase inhibitors

Nature Chemical Biology, Journal Year: 2023, Volume and Issue: 20(5), P. 577 - 585

Published: Oct. 30, 2023

Abstract Medicinal chemistry has discovered thousands of potent protein and lipid kinase inhibitors. These may be developed into therapeutic drugs or chemical probes to study biology. Because polypharmacology, a large part the human kinome currently lacks selective probes. To discover such probes, we profiled 1,183 compounds from drug discovery projects in lysates cancer cell lines using Kinobeads. The resulting 500,000 compound–target interactions are available ProteomicsDB exemplify how this molecular resource used. For instance, data revealed several hundred reasonably for 72 kinases. Cellular assays validated GSK986310C as candidate SYK (spleen tyrosine kinase) probe X-ray crystallography uncovered structural basis observed selectivity CK2 inhibitor GW869516X. Compounds targeting PKN3 were phosphoproteomics identified substrates that indicate target engagement cells. We anticipate will aid research

Language: Английский

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The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

Molecules, Journal Year: 2023, Volume and Issue: 28(14), P. 5359 - 5359

Published: July 12, 2023

The altered activation or overexpression of protein kinases (PKs) is a major subject research in oncology and their inhibition using small molecules, inhibitors (PKI) the best available option for cure cancer. pyrazole ring extensively employed field medicinal chemistry drug development strategies, playing vital role as fundamental framework structure various PKIs. This scaffold holds importance considered privileged based on its synthetic accessibility, drug-like properties, versatile bioisosteric replacement function. It has proven to play key many PKI, such Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, RET. Of 74 molecule PKI approved by US FDA, 8 contain ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, Ruxolitinib. focus this review unfused within clinically tested additional required elements chemical structures. Related important fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, pyrazolo[3,4-d]pyrimidine are beyond work.

Language: Английский

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Applications of palladium-catalyzed C–N cross-coupling reactions in pharmaceutical compounds

RSC Advances, Journal Year: 2023, Volume and Issue: 13(27), P. 18715 - 18733

Published: Jan. 1, 2023

C–N cross-coupling bond formation reactions have become valuable approaches to synthesizing anilines and their derivatives which are known as important chemical compounds.

Language: Английский

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The role of the methoxy group in approved drugs

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 273, P. 116364 - 116364

Published: April 4, 2024

Language: Английский

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Chemoproteomics Identifies State-Dependent and Proteoform-Selective Caspase-2 Inhibitors

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(22), P. 14972 - 14988

Published: May 24, 2024

Caspases are a highly conserved family of cysteine-aspartyl proteases known for their essential roles in regulating apoptosis, inflammation, cell differentiation, and proliferation. Complementary to genetic approaches, small-molecule probes have emerged as useful tools modulating caspase activity. However, due the high sequence structure homology all 12 human caspases, achieving selectivity remains central challenge caspase-directed inhibitor development efforts. Here, using mass spectrometry-based chemoproteomics, we first identify reactive noncatalytic cysteine that is unique caspase-2. By combining both gel-based activity-based protein profiling (ABPP) tobacco etch virus (TEV) protease activation assay, then covalent lead compounds react preferentially with this afford complete blockade caspase-2 Inhibitory activity restricted zymogen or precursor form monomeric Focused analogue synthesis combined chemoproteomic target engagement analysis cellular lysates cells yielded pan-caspase-reactive molecules selective together structurally matched inactive control. Application focused set tool stratify functions partially processed (p32) forms provide evidence support caspase-2-mediated response DNA damage largely driven by p32 enzyme. More broadly, our study highlights future opportunities proteoform-selective inhibitors nonconserved residues.

Language: Английский

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Kinase Inhibitors FDA Approved 2018–2023: Drug Targets, Metabolic Pathways, and Drug-Induced Toxicities

Drug Metabolism and Disposition, Journal Year: 2024, Volume and Issue: 52(6), P. 479 - 492

Published: Jan. 29, 2024

Small molecule kinase inhibitors are one of the fastest growing classes drugs, which approved by US Food and Drug Administration (FDA) for cancer non-cancer indications. As September 2023, there were over 70 FDA-approved small on market, 42 in past five years (2018-2023). This minireview discusses recent advances our understanding pharmacology, metabolism, toxicity profiles recently with a central focus tyrosine (TKIs). In this we discuss most common therapeutic indications molecular target(s) 2018-2023. We also describe unique aspects bioactivation, drug-drug interaction (DDI) potential inhibitors; drug concerns related to inhibitors, such as drug-induced liver injury; highlight clinical outcomes challenges relevant TKI therapy. Case examples provided targets, metabolism pathways, DDI potential, risks serious adverse reactions. The concludes discussion perspectives future research optimize therapy maximize efficacy minimize toxicity. Significance Statement highlights important pharmacology toxicology key targets major pathways TKIs discussed. Clinically case that demonstrate risk hepatotoxic interactions involving co-administered drugs.

Language: Английский

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A green bioanalytical spectrofluorimetric approach for estimation of Avapritinib anti-tumor drug; application to quality control and clinical studies

Bioanalysis, Journal Year: 2025, Volume and Issue: 17(1), P. 31 - 40

Published: Jan. 2, 2025

Gastrointestinal stromal tumors (GISTs) account for about 80% of the mesenchymal GI tract. About 5000-6000 patients are diagnosed in United States (US) alone, and up to 14.5 cases per million discovered Europe annually. Avapritinib (AVP) is a potent selective targeted medication that has been recently approved, by US Food Drug Administration, 2020 treatment GISTs. AVP currently considered first-line mutant GIST, which resistant other medications. This turn stimulates need fast, green, efficient methods routine estimation quality control clinical studies. The proposed approach designs spectrofluorimetric tool estimate different matrices, based on nucleophilic substitution reaction. A highly fluorescent product was measured at 535 nm following excitation 470 nm. research procedure bioanalytically validated within range between 80 900 ng mL-1, where limit quantitation (LOQ) 15.78 mL-1. developed successfully applied investigate content uniformity testing tablet dosage forms, biological plasma pharmacokinetic study. could be recommended therapeutic drug monitoring.

Language: Английский

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4,6-Disubstituted pyrimidine-based microtubule affinity-regulating kinase 4 (MARK4) inhibitors: synthesis, characterization, in-vitro activity and in-silico studies

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 20, 2025

Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder that significantly impacts the cognitive function and memory of person. Despite significant research efforts, ability to completely prevent or effectively treat AD its related dementias remains limited. Protein kinases are integral pathology represent promising targets for therapeutic intervention. Methods A series pyrimidine-based compounds 4-(4-(arylsulfonyl)piperazin-1-yl)-6-(thiophen-3-yl)pyrimidine derivatives ( 8 - 14 ) were synthesized characterised. ATPase inhibition was carried out against MARK4 enzyme. Molecular docking molecular dynamics (MD) simulation at 500 ns (PDB: 5ES1). The drug-likeness feature toxicity molecules evaluated using QikProp other tools. Results Compounds following multi-step approach characterized multi-nuclear magnetic resonance 1 H/ 13 C-NMR) mass spectrometry. assay showed an IC 50 value in micromolar (μM) range. results studies consistent with in-vitro experiments identified 9 as candidates highest affinity towards MARK4. MD further supported these results, showing binding ligands stabilises target protein. Conclusion Using experimental theoretical approaches, we demonstrated reported class pyrimidine excellent starting point developing next-generation anti-AD drugs.

Language: Английский

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