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1.
J Enzyme Inhib Med Chem ; 39(1): 2295241, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38134358

RESUMEN

Colorectal cancer (CRC) is one of the most common cancers worldwide. Nowadays, owing to the complex mechanism of tumorigenesis, simultaneous inhibition of multiple targets is an important anticancer strategy. Recent studies have demonstrated receptor tyrosine kinase AXL (AXL) and histone deacetylase 2 (HDAC2) are closely associated with colorectal cancer. Herein, we identified five hit compounds concurrently targeting AXL and HDAC2 using virtual screening. Inhibitory experiments revealed these hit compounds potently inhibited AXL and HDAC2 in the nanomolar range. Among them, Hit-3 showed the strongest inhibitory effects which were better than that of the positive control groups. Additionally, MD assays showed that Hit-3 could bind stably to the AXL and HDAC2 active pockets. Further MTT assays demonstrated that Hit-3 showed potent anti-proliferative activity. Most importantly, Hit-3 exhibited significant in vivo antitumor efficacy in xenograft models. Collectively, this study is the first discovery of dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment.


Asunto(s)
Neoplasias Colorrectales , Simulación de Dinámica Molecular , Humanos , Simulación del Acoplamiento Molecular , Farmacóforo , Histona Desacetilasa 2/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Detección Precoz del Cáncer , Neoplasias Colorrectales/tratamiento farmacológico
2.
J Enzyme Inhib Med Chem ; 38(1): 2241118, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37528657

RESUMEN

Prostate cancer (PCa) is a clinically heterogeneous disease with a progressively increasing incidence. Concurrent inhibition of coactivator-associated arginine methyltransferase 1 (CARM1) and histone deacetylase 2 (HDAC2) could potentially be a novel strategy against PCa. Herein, we identified seven compounds simultaneously targeting CARM1 and HDAC2 through structure-based virtual screening. These compounds possessed potent inhibitory activities at the nanomolar level in vitro. Among them, CH-1 was the most active inhibitor which exhibited excellent and balanced inhibitory effects against both CARM1 (IC50 = 3.71 ± 0.11 nM) and HDAC2 (IC50 = 4.07 ± 0.25 nM). MD simulations presented that CH-1 could stably bind the active pockets of CARM1 and HDAC2. Notably, CH-1 exhibited strong anti-proliferative activity against multiple prostate-related tumour cells (IC50 < 1 µM). In vivo, assessment indicated that CH-1 significantly inhibited tumour growth in a DU145 xenograft model. Collectively, CH-1 could be a promising drug candidate for PCa treatment.


Asunto(s)
Antineoplásicos , Neoplasias de la Próstata , Masculino , Humanos , Histona Desacetilasa 2/metabolismo , Antineoplásicos/farmacología , Proteína-Arginina N-Metiltransferasas/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Inhibidores de Histona Desacetilasas/farmacología
3.
J Enzyme Inhib Med Chem ; 38(1): 2220558, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37357755

RESUMEN

Heat shock protein 90 (Hsp90) is considered an attractive therapeutic target for cancer treatment due to its high expression in many cancers. In this study, four potent Hsp90 inhibitors (HPs 1-4) were identified using structure-based virtual screening. Among them, HP-4 exhibited the most potent inhibitory effects (IC50 = 17.64 ± 1.45 nM) against the Hsp90 protein, which was about 7.7 times stronger than that of MPC-3100 (a positive inhibitor targeting Hsp90). In vitro cytotoxicity assay suggested that HP-4 could effectively inhibit the proliferation of a series of tumour cells, including HCT-116, HeLa, A549, A2780, DU145, HepG2 and A498. Furthermore, in vivo assay displayed that HP-4 had significant anti-tumour effects on HCT-116 cell-derived xenograft models. These data demonstrate that HP-4 could be a potential lead compound for the further investigation of anti-tumour drugs.


Asunto(s)
Descubrimiento de Drogas , Proteínas HSP90 de Choque Térmico , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos/métodos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular , Farmacóforo , Humanos , Animales , Ratones
4.
J Am Chem Soc ; 144(16): 7117-7128, 2022 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-35417174

RESUMEN

The application of peptide drugs in cancer therapy is impeded by their poor biostability and weak cell permeability. Therefore, it is imperative to find biostable and cell-permeable peptide drugs for cancer treatment. Here, we identified a potent, selective, biostable, and cell-permeable cyclic d-peptide, NKTP-3, that targets NRP1 and KRASG12D using structure-based virtual screening. NKTP-3 exhibited strong biostability and cellular uptake ability. Importantly, it significantly inhibited the growth of A427 cells with the KRASG12D mutation. Moreover, NKTP-3 showed strong antitumor activity against A427 cell-derived xenograft and KRASG12D-driven primary lung cancer models without obvious toxicity. This study demonstrates that the dual NRP1/KRASG12D-targeting cyclic d-peptide NKTP-3 may be used as a potential chemotherapeutic agent for KRASG12D-driven lung cancer treatment.


Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Neoplasias Pulmonares/patología , Mutación , Péptidos/genética , Proteínas Proto-Oncogénicas p21(ras)/genética
5.
Mol Phylogenet Evol ; 166: 107329, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34678410

RESUMEN

The papilionoid legume genus Ormosia (Fabaceae) comprises about 150 species of trees and exhibits a striking disjunct geographical distribution between the New World- and Asian and Australasian wet tropics and subtropics. Modern classifications of Ormosia are not grounded on a well-substantiated phylogenetic hypothesis and have been limited to just portions of the geographical range of the genus. The lack of an evolutionarily-based foundation for systematic studies has hindered taxonomic work on the genus and prevented the testing of biogeographical hypotheses related to the origin of the Old World/New World disjunction and the individual dispersal histories within both areas. Here, we present the most comprehensively sampled molecular phylogeny of Ormosia to date, based on analysis of both nuclear (ITS) and plastid (matK and trnL-F) DNA sequences from 82 species of the genus. Phylogenetically-based divergence times and ancestral range estimations are employed to test hypotheses related to the biogeographical history of the genus. We find strong support for the monophyly of Ormosia and the grouping of all sampled Asian species of the genus into two comparably sized clades, one of which is sister to another large clade containing all sampled New World species. Within the New World clade, additional resolution supports the grouping of most species into three mutually exclusive subordinate clades. The remaining New World species form a fourth well-supported clade in the analyses of plastid sequences, but that result is contradicted by the analysis of ITS. With few exceptions the supported clades have not been previously recognized as taxonomic groups. The biogeographical analysis suggests that Ormosia originated in continental Asia and dispersed to the New World in the Oligocene or early Miocene via long-distance trans-oceanic dispersal. We reject the hypothesis that the inter-hemispheric disjunction in Ormosia resulted from fragmentation of a more continuous "Boreotropical" distribution since the dispersal post-dates Eocene climatic maxima. Both of the Old World clades appear to have originated in mainland Asia and subsequently dispersed into the Malay Archipelago and beyond, at least two lineages dispersing across Wallace's Line as far as the Solomon Islands and northeastern Australia. In the New World, the major clades all originated in Amazonia. Dispersal from Amazonia into peripheral areas in Central America, the Caribbean, and Extra-Amazonian Brazil occurred multiple times over varying time scales, the earliest beginning in the late Miocene. In a few cases, these dispersals were followed by local diversification, but not by reverse migration back to Amazonia. Within each of the two main areas of distribution, multiple modest bouts of oceanic dispersal were required to achieve the modern distributions.


Asunto(s)
Fabaceae , Teorema de Bayes , Evolución Biológica , Fabaceae/genética , Filogenia , Filogeografía , Plastidios/genética
6.
J Clin Lab Anal ; 36(1): e24097, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34837265

RESUMEN

BACKGROUND: Carotid atherosclerosis (CAS) is associated with increased cardiovascular risk and implicated in 20-30% of strokes. METHODS: 504 patients were included in this study. The detailed medical history and the results of physical examination, carotid ultrasound examination, and routine laboratory tests were collected. Logistic regression analyses were conducted to analyze the relationship between the SUA and the presence of carotid plaques. And the relationship between SUA and the progression of CAS was analyzed by multiple linear regression. The effect of hormone replacement therapy (HRT) on CAS has also be evaluated. RESULTS: 412 patients (81.7%) had carotid plaques of different sizes by carotid ultrasound examination. We found a positive association between the level of SUA and the probability of having carotid plaque by univariate logistic regression (OR: 2.01, 95% CI: 1.83-2.19, p = 0.003). At 2 years post-discharge, we found that 1 mg/dL increase in SUA levels was expected to 0.946% increase in plaque score and 0.026 cm increase in carotid intima-media thickness, separately. Moreover, patients treated by long-term HRT (≥5 years) had a lower level of SUA and blood lipid and the less change of plaque score and carotid intima-media thickness than patients without HRT. CONCLUSION: The presence and progression of CAS had significantly positive associations with the level of SUA. And the HRT may have the ability to prevent the presence and progression of CAS. However, the safety and long-term outcome of HRT on CAS should be evaluated in further studies.


Asunto(s)
Enfermedades de las Arterias Carótidas , Posmenopausia/sangre , Ácido Úrico/sangre , Anciano , Atención Ambulatoria , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/epidemiología , Enfermedades de las Arterias Carótidas/patología , Femenino , Estudios de Seguimiento , Terapia de Reemplazo de Hormonas/estadística & datos numéricos , Humanos
7.
Molecules ; 24(17)2019 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-31480625

RESUMEN

Tubulin inhibitors have been considered as potential drugs for cancer therapy. However, their drug resistance and serious side-effects are the main reasons for clinical treatment failure. Therefore, there is still an urgent need to develop effective therapeutic drugs. Herein, a structure-based pharmacophore model was developed based on the co-crystallized structures of the tubulin with a high resolution. The model including one hydrogen-bond acceptor feature, two aromatic features, and one hydrophobic feature was further validated using the Gunner-Henry score method. Virtual screening was performed by an integrated protocol that combines drug-likeness analysis, pharmacophore mapping, and molecular docking approaches. Finally, five hits were selected for biological evaluation. The results indicated that all these hits at the concentration of 40 µM showed an inhibition of more than 50% against five human tumor cells (MCF-7, U87MG, HCT-116, MDA-MB-231, and HepG2). Particularly, hit 1 effectively inhibited the proliferation of these tumor cells, with inhibition rates of more than 80%. The results of tubulin polymerization and colchicine-site competition assays suggested that hit 1 significantly inhibited tubulin polymerization by binding to the colchicine site. Thus, hit 1 could be used as a potential chemotherapeutic agent for cancer treatment. This work also demonstrated the potential of our screening protocol to identify biologically active compounds.


Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Relación Estructura-Actividad Cuantitativa , Moduladores de Tubulina/farmacología , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colchicina/metabolismo , Humanos , Ligandos , Modelos Moleculares , Polimerizacion , Tubulina (Proteína)/metabolismo
8.
Molecules ; 24(23)2019 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-31795214

RESUMEN

Polo-box domain of polo-like kinase 1 (PLK1-PBD) has a pivotal role in cell proliferation and could be implicated as a potential anticancer target. Although some small-molecule inhibitors have been developed, their clinical application has been restricted by the poor selectivity. Therefore, there is an urgent need to develop effective PLK1-PBD inhibitors. Herein, we have developed a virtual screening protocol to find PLK1-PBD inhibitors by using combination of structure-based pharmacophore modeling and molecular docking. This protocol was successfully applied to screen PLK1-PBD inhibitors from specs database. MTT assay indicated that five screened hits suppressed the growth of HeLa cells. Particularly, hit-5, as a selective PLK1 inhibitor targeting PLK1-PBD, significantly inhibited the progression of HeLa cells-derived xenograft, with no obvious side effects. This work demonstrates that hit-5 may be a potential anticancer agent.


Asunto(s)
Antineoplásicos/química , Proteínas de Ciclo Celular/química , Diseño de Fármacos , Modelos Moleculares , Dominios y Motivos de Interacción de Proteínas , Proteínas Serina-Treonina Quinasas/química , Proteínas Proto-Oncogénicas/química , Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Relación Estructura-Actividad , Quinasa Tipo Polo 1
9.
Molecules ; 24(23)2019 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-31766720

RESUMEN

Poly (ADP-ribose) polymerase-1 (PARP-1) plays critical roles in many biological processes and is considered as a potential target for anticancer therapy. Although some PARP-1 inhibitors have been reported, their clinical application in cancer therapy is limited by some shortcomings such as weak affinity, low selectivity and adverse side effects. To identify highly potent and selective PARP-1 inhibitors, an integrated protocol that combines pharmacophore mapping, virtual screening and molecular docking was constructed. It was then used as a screening query to identify potent leads with unknown scaffolds from an in-house database. Finally, four retrieved compounds were selected for biological evaluation. Biological testing indicated that the four compounds showed strong inhibitory activities on the PARP-1 (IC50 < 0.2 µM). MTT assay confirmed that compounds 1-4 inhibited the growth of human lung cancer A549 cells in a dose-dependent manner. The obtained compounds from this study may be potential leads for PARP-1 inhibition in the treatment of cancer.


Asunto(s)
Neoplasias Pulmonares/enzimología , Poli(ADP-Ribosa) Polimerasa-1/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Células A549 , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Modelos Moleculares , Simulación del Acoplamiento Molecular , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Relación Estructura-Actividad
10.
Molecules ; 25(1)2019 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-31892137

RESUMEN

The polo-box domain of polo-like kinase 1 (PLK1-PBD) is proved to have crucial roles in cell proliferation. Designing PLK1-PBD inhibitors is challenging due to their poor cellular penetration. In this study, we applied a virtual screening workflow based on a combination of structure-based pharmacophore modeling with molecular docking screening techniques, so as to discover potent PLK1-PBD peptide inhibitors. The resulting 9 virtual screening peptides showed affinities for PLK1-PBD in a competitive binding assay. In particular, peptide 5 exhibited an approximately 100-fold increase in inhibitory activity (IC50 = 70 nM), as compared with the control poloboxtide. Moreover, cell cycle experiments indicated that peptide 5 effectively inhibited the expression of p-Cdc25C and cell cycle regulatory proteins by affecting the function of PLK1-PBD, thereby inducing mitotic arrest at the G2/M phase. Overall, peptide 5 can serve as a potent lead for further investigation as PLK1-PBD inhibitors.


Asunto(s)
Proteínas de Ciclo Celular , División Celular/efectos de los fármacos , Fase G2/efectos de los fármacos , Simulación del Acoplamiento Molecular , Péptidos , Inhibidores de Proteínas Quinasas , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Evaluación de Medicamentos , Células HeLa , Humanos , Péptidos/química , Péptidos/farmacología , Dominios Proteicos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas/metabolismo , Relación Estructura-Actividad , Quinasa Tipo Polo 1
11.
Bioorg Med Chem ; 26(12): 3429-3437, 2018 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-29807699

RESUMEN

Polo-like kinase 1 (Plk1) is an anti-cancer target due to its critical role in mitotic progression. A growing body of evidence has documented that Peptide-Plk1 inhibitors showed high Plk1 binding affinity. However, phosphopeptides-Plk1 inhibitors showed poor cell membranes permeability, which limits their clinical applications. In current study, nine candidate phosphopeptides consisting of non-natural amino acids were rationally designed and then successfully synthesized using an Fmoc-solid phase peptide synthesis (SPPS) strategy. Moreover, the binding affinities and selectivity were evaluated via fluorescence polarization (FP) assay. The results confirmed that the most promising phosphopeptide 6 bound to Plk1 PBD with the IC50 of 38.99 nM, which was approximately 600-fold selectivity over Plk3 PBD (IC50 = 25.44 µM) and nearly no binding to Plk2 PBD. Furthermore the intracellular activities and the cell membrane permeability of phosphopeptide 6 were evalutated. Phosphopeptide 6 demonstrated appropriate cell membrane permeability and arrested HeLa cells cycle in G2/M phase by regulating CyclinB1-CDK1. Further, phosphopeptide 6 showed typical apoptotic morphology and induced caspase-dependent apoptosis. In conclusion, we expect our discovery can provide new insights into the further optimization of Plk1 PBD inhibitors.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Diseño de Fármacos , Fosfopéptidos/química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Secuencia de Aminoácidos , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Proteínas de Ciclo Celular/metabolismo , Permeabilidad de la Membrana Celular/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HeLa , Humanos , Fosfopéptidos/metabolismo , Fosfopéptidos/farmacología , Unión Proteica , Dominios Proteicos , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Supresoras de Tumor , Quinasa Tipo Polo 1
12.
Cell Microbiol ; 17(3): 408-24, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25293534

RESUMEN

Intracellular bacterial pathogens including Shigella, Listeria, Mycobacteria, Rickettsia and Burkholderia spp. deploy a specialized surface protein onto one pole of the bacteria to induce filamentous actin tail formation for directional movement within host cytosol. The mechanism underlying polar targeting of the actin tail proteins is unknown. Here we perform a transposon screen in Burkholderia thailandensis and identify a conserved bimC that is required for actin tail formation mediated by BimA from B. thailandensis and its closely related pathogenic species B. pseudomallei and B. mallei. bimC is located upstream of bimA in the same operon. Loss of bimC results in even distribution of BimA on the outer membrane surface, where actin polymerization still occurs. BimC is targeted to the same bacterial pole independently of BimA. BimC confers polar targeting of BimA prior to BimA translocation across bacterial inner membrane. BimC is an iron-binding protein, requiring a four-cysteine cluster at the carboxyl terminus. Mutation of the cysteine cluster disrupts BimC polar localization. Truncation analyses identify the transmembrane domain in BimA being responsible for its polar targeting. Consistently, BimC can interact with BimA transmembrane domain in an iron binding-dependent manner. Our study uncovers a new mechanism that determines the polar distribution of bacteria-induced actin tail in infected host cells.


Asunto(s)
Actinas/metabolismo , Burkholderia/metabolismo , Proteínas de Unión a Hierro/metabolismo , Proteínas de Microfilamentos/metabolismo , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Burkholderia/genética , Análisis Mutacional de ADN , Elementos Transponibles de ADN , Eliminación de Gen , Proteínas de Microfilamentos/genética , Mutagénesis Insercional , Operón , Unión Proteica , Mapeo de Interacción de Proteínas , Transporte de Proteínas
13.
Acta Pharmacol Sin ; 35(7): 967-79, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24909516

RESUMEN

AIM: To construct a quantitative pharmacophore model of tubulin inhibitors and to discovery new leads with potent antitumor activities. METHODS: Ligand-based pharmacophore modeling was used to identify the chemical features responsible for inhibiting tubulin polymerization. A set of 26 training compounds was used to generate hypothetical pharmacophores using the HypoGen algorithm. The structures were further validated using the test set, Fischer randomization method, leave-one-out method and a decoy set, and the best model was chosen to screen the Specs database. Hit compounds were subjected to molecular docking study using a Molecular Operating Environment (MOE) software and to biological evaluation in vitro. RESULTS: Hypo1 was demonstrated to be the best pharmacophore model that exhibited the highest correlation coefficient (0.9582), largest cost difference (70.905) and lowest RMSD value (0.6977). Hypo1 consisted of one hydrogen-bond acceptor, a hydrogen-bond donor, a hydrophobic feature, a ring aromatic feature and three excluded volumes. Hypo1 was validated with four different methods and had a goodness-of-hit score of 0.81. When Hypo1 was used in virtual screening of the Specs database, 952 drug-like compounds were revealed. After docking into the colchicine-binding site of tubulin, 5 drug-like compounds with the required interaction with the critical amino acid residues and the binding free energies < -4 kcal/mol were selected as representative leads. Compounds 1 and 3 exhibited inhibitory activity against MCF-7 human breast cancer cells in vitro. CONCLUSION: Hypo1 is a quantitative pharmacophore model for tubulin inhibitors, which not only provides a better understanding of their interaction with tubulin, but also assists in discovering new potential leads with antitumor activities.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Simulación del Acoplamiento Molecular , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/metabolismo , Algoritmos , Mama/efectos de los fármacos , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Femenino , Humanos , Programas Informáticos , Relación Estructura-Actividad , Tubulina (Proteína)/química
14.
Biomed Pharmacother ; 177: 116839, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38889633

RESUMEN

Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) and histone deacetylase 8 (HDAC8) have been shown to be associated with the development of several cancers. Here, we identified a dual-target DYRK2/HDAC8 inhibitor (DYC-1) through a combined virtual screening protocol. DYC-1 exhibited nanomolar inhibitory activity against both DYRK2 (IC50 = 5.27 ± 0.13 nM) and HDAC8 (IC50 = 8.06 ± 0.47 nM). Molecular dynamics simulations showed that DYC-1 had positive binding stability with DYRK2 and HDAC8. Importantly, the cytotoxicity assay indicated that DYC-1 exhibited superior antiproliferative activity against human liver cancer, especially SK-HEP-1 cells, and had no significant inhibition on normal liver cells. Moreover, DYC-1 showed a strong inhibitory effect on the growth of SK-HEP-1 xenograft tumors with no significant side effects. These data suggest that DYC-1 is a high-efficacy and low-toxic antitumor agent for the treatment of hepatocellular carcinoma.


Asunto(s)
Carcinoma Hepatocelular , Quinasas DyrK , Histona Desacetilasas , Neoplasias Hepáticas , Ratones Desnudos , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Proteínas Represoras , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Animales , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Histona Desacetilasas/metabolismo , Línea Celular Tumoral , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/uso terapéutico , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Ratones , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Descubrimiento de Drogas , Simulación de Dinámica Molecular
15.
Foods ; 13(17)2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39272565

RESUMEN

To expand the development of characteristic extension products of Yunnan tea and improve the utilization rate of Yunnan tea resources, in this study, we compared the metabolite composition among raw Pu-erh tea, ripe Pu-erh tea prepared with glutinous rice (according to tea to glutinous rice ratio of 1:3), and ripe Pu-erh tea prepared with a mixture of sorghum, rice, glutinous rice, wheat, and corn as raw materials (according to a tea to glutinous rice ratio of 1:3). Rice flavor liquor prepared with 100% glutinous rice served as a control. The raw Pu-erh tea liquor (RAWJ), ripe Pu-erh tea liquor (RIPEJ), ripe Pu-erh tea mixed grain liquor (HHLSJ), and rice-flavor liquor (MJ) were all brewed by semi-solid fermentation. The non-volatile components of the liquor samples were analyzed by ultra-high-performance liquid chromatography-tandem mass spectrometry as a broadly targeted metabolomics technique. A total of 691 metabolites were identified from the four samples. Among them, 674, 671, 633, and 667 species were detected in RAWJ, RIPEJ, HHLSJ, and MJ samples, respectively. Venn diagram analysis demonstrated 19, 21, and 14 unique metabolites in RAWJ, RIPEJ, and HHLSJ, respectively, compared with the metabolite composition of MJ. Flavonoids are the most important differential metabolite between tea liquor and rice-flavor liquor. This study provides a theoretical basis for the development of tea liquor products and offers insight into the difference in non-volatile components between tea liquor and rice-flavor liquor.

16.
Front Pharmacol ; 15: 1454523, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39351092

RESUMEN

Background: Overexpression of monopolar spindle 1 (MPS1) and histone deacetylase 8 (HDAC8) is associated with the proliferation of liver cancer cells, so simultaneous inhibition of both MPS1 and HDAC8 could offer a promising therapeutic approach for the treatment of liver cancer. Dual-targeted MPS1/HDAC8 inhibitors have not been reported. Methods: A combined approach of pharmacophore modeling and molecular docking was used to identify potent dual-target inhibitors of MPS1 and HDAC8. Enzyme inhibition assays were performed to evaluate the optimal compound with the strongest inhibitory activity against MPS1 and HDAC8. The selectivity of MPH-5 for MPS1 and HDAC8 was assessed on a panel of 68 kinases and other histone deacetylases. Subsequently, molecular dynamics (MD) simulation verified the binding stability of the optimal compound to MPS1 and HDAC8. Ultimately, in vitro cellular assays and in vivo antitumor assays evaluated the antitumor efficacy of the most promising compound for the treatment of hepatocellular carcinoma. Results: Six dual-target compounds (MPHs 1-6) of both MPS1 and HDAC8 were identified from the database using a combined virtual screening protocol. Notably, MPH-5 showed nanomolar inhibitory effect on both MPS1 (IC50 = 4.52 ± 0.21 nM) and HDAC8 (IC50 = 6.07 ± 0.37 nM). MD simulation indicated that MPH-5 stably binds to both MPS1 and HDAC8. Importantly, cellular assays revealed that MPH-5 exhibited significant antiproliferative activity against human liver cancer cells, especially HepG2 cells. Moreover, MPH-5 exhibited low toxicity and high efficacy against tumor cells, and it overcomes drug resistance to some extent. In addition, MPH-5 may exert its antitumor effects by downregulating MPS1-driven phosphorylation of histone H3 and upregulating HDAC8-mediated K62 acetylation of PKM2. Furthermore, MPH-5 showed potent inhibition of HepG2 xenograft tumor growth in mice with no apparent toxicity and presented favorable pharmacokinetics. Conclusion: The study suggests that MPH-5 is a potent, selective, high-efficacy, and low-toxicity antitumor candidate for the treatment of hepatocellular carcinoma.

17.
Biomolecules ; 14(9)2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39334872

RESUMEN

Tea (Camellia sinensis) falls into the family Theaceae, is a valuable commercial crop, and tea products made from its buds and young leaves are favored by consumers all over the world. The more common Thea plant is Camellia sinensis (C. sinensis), but its most important relative, Camellia taliensis (C. taliensis), is also utilized by locals in the area of cultivation to manufacture tea. In this investigation, C. taliensis (DL) and C. sinensis (QJZ) were characterized in terms of their agronomic traits, physicochemical indices, metabolomics, and transcriptomics. The leaf area of DL is larger than that of QJZ; the color of DL's buds and leaves is yellowish-green, while that of QJZ's is green. DL's buds and leaves are more densely velvety than those of QJZ. The HPLC results indicated that the physicochemical contents varied considerably between the two samples, with DL having greater concentrations of EGCG and GABA than QJZ, while QJZ had remarkably higher concentrations of C, CA, and EGC than DL. A total of 2269 metabolites and 362,190,414 genes were positively identified, with the number of DAMs and DEGs being 1001 and 34,026, respectively. The flavonoids, phenolic acids, and alkaloid metabolites were dramatically different between the two tea group plants. Bioinformatics profiling revealed that the DAMs and DEGs of the two tea group plants interacted with each other and were involved in metabolic pathways, including "biosynthesis of secondary metabolites", "biosynthesis of amino acids", "biosynthesis of cofactors", "phenylpropanoid biosynthesis", and "flavonoid biosynthesis". Overall, these results provide statistical support for germplasm conservation and production for both C. taliensis and C. sinensis.


Asunto(s)
Camellia , Metabolómica , Hojas de la Planta , Camellia/genética , Camellia/metabolismo , Hojas de la Planta/metabolismo , Hojas de la Planta/genética , Transcriptoma/genética , Catequina/metabolismo , China , Perfilación de la Expresión Génica , Camellia sinensis/genética , Camellia sinensis/metabolismo , Regulación de la Expresión Génica de las Plantas , Metaboloma , Ácido gamma-Aminobutírico/metabolismo
18.
Eur J Med Chem ; 263: 115908, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-37981444

RESUMEN

The efficacy of approved vaccines has been diminishing due to the increasing advent of SARS-CoV-2 variants with diverse mutations that favor sneak entry. Nonetheless, these variants recognize the conservative host receptors angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1) for entry, rendering the dual blockade of ACE2 and NRP1 an advantageous pan-inhibition strategy. Here, we identified a highly potent dual-targeting peptide AP-1 using structure-based virtual screening protocol. AP-1 had nanoscale binding affinities for ACE2 (Kd = 6.1 ± 0.2 nM) and NRP1 (Kd = 13.4 ± 1.2 nM) and approximately 102- and 8-fold stronger than positive inhibitors S471-503 and NMTP-5, respectively. Further evidence in pseudovirus cell infection and cytotoxicity assays demonstrated that AP-1 exhibited remarkable entry inhibition of variants of concern (VOCs) of SARS-CoV-2 without impairing host cell viability. Together, our findings suggest that AP-1 with dual-targeting ACE2/NRP1 efficacy could be a promising broad-spectrum agent for treating SARS-CoV-2 emerging VOCs.


Asunto(s)
COVID-19 , Humanos , SARS-CoV-2/fisiología , Enzima Convertidora de Angiotensina 2 , Neuropilina-1/metabolismo , Factor de Transcripción AP-1/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Unión Proteica , Péptidos/metabolismo
19.
J Med Chem ; 67(9): 7130-7145, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38630077

RESUMEN

Multitarget medications represent an appealing therapy against the disease with multifactorial abnormalities─cancer. Therefore, simultaneously targeting son of sevenless 1 (SOS1) and epidermal growth factor receptor (EGFR), two aberrantly expressed proteins crucial for the oncogenesis and progression of prostate cancer, may achieve active antitumor effects. Here, we discovered dual SOS1/EGFR-targeting compounds via pharmacophore-based docking screening. The most prominent compound SE-9 exhibited nanomolar inhibition activity against both SOS1 and EGFR and efficiently suppressed the phosphorylation of ERK and AKT in prostate cancer cells PC-3. Cellular assays also revealed that SE-9 displayed strong antiproliferative activities through diverse mechanisms, such as induction of cell apoptosis and G1 phase cell cycle arrest, as well as reduction of angiogenesis and migration. Further in vivo findings showed that SE-9 potently inhibited tumor growth in PC-3 xenografts without obvious toxicity. Overall, SE-9 is a novel dual-targeting SOS1/EGFR inhibitor that represents a promising treatment strategy for prostate cancer.


Asunto(s)
Antineoplásicos , Proliferación Celular , Receptores ErbB , Neoplasias de la Próstata , Proteína SOS1 , Masculino , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Proteína SOS1/antagonistas & inhibidores , Proteína SOS1/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Ratones , Apoptosis/efectos de los fármacos , Descubrimiento de Drogas , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratones Desnudos , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos BALB C
20.
Zhong Yao Cai ; 36(5): 691-5, 2013 May.
Artículo en Zh | MEDLINE | ID: mdl-24218955

RESUMEN

OBJECTIVE: In contrast to the newly-planted plants, through measuring and analyzing the chlorophyll content, photosynthetic characteristics, root activity and enzyme activity of Rehmannia glutinosa in growth stages, the differentiation manifestation of R. glutinosa physiological activity mediated by continuous cropping was studied. METHODS: SPAD-502 chlorophyll meter was used to measure chlorophyll content and LI-6400 portable photosynthetic apparatus to determine plant photosynthetic characteristics. Plant root vigor and enzyme system were measured following reference literature. RESULTS: The problems of Rehmannia caused by continuous cropping had happened since the early stage of its growth period, and lasted throughout the whole growth period. Under the condition of continuous cropping, the chlorophyll content, photosynthetic characteristics and root activity remained at a lower level compared with the newly-planted plants, among which, the chlorophyll content and the root activity (100 days after planting) had significant differences. CONCLUSION: The insufficient photosynthesis source and the reducing of the storage capacity (root tuber) under the condition of continuous cropping might be the main reasons for these problems of R. glutinosa.


Asunto(s)
Agricultura/métodos , Clorofila/análisis , Fotosíntesis/fisiología , Raíces de Plantas/fisiología , Rehmannia/crecimiento & desarrollo , Peroxidasas/metabolismo , Raíces de Plantas/metabolismo , Rehmannia/metabolismo , Rehmannia/fisiología , Estrés Fisiológico
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