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1.
J Med Chem ; 67(8): 6425-6455, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38613499

RESUMO

The RAS-RAF-MEK-ERK signaling cascade is abnormally activated in various tumors, playing a crucial role in mediating tumor progression. As the key component at the terminal stage of this cascade, ERK1/2 emerges as a potential antitumor target and offers a promising therapeutic strategy for tumors harboring BRAF or RAS mutations. Here, we identified 36c with a (thiophen-3-yl)aminopyrimidine scaffold as a potent ERK1/2 inhibitor through structure-guided optimization for hit 18. In preclinical studies, 36c showed powerful ERK1/2 inhibitory activities (ERK1/2 IC50 = 0.11/0.08 nM) and potent antitumor efficacy both in vitro and in vivo against triple-negative breast cancer and colorectal cancer models harboring BRAF and RAS mutations. 36c could directly inhibit ERK1/2, significantly block the phosphorylation expression of their downstream substrates p90RSK and c-Myc, and induce cell apoptosis and incomplete autophagy-related cell death. Taken together, this work provides a promising ERK1/2 lead compound for multiple tumor-treatment drug discovery.


Assuntos
Antineoplásicos , Inibidores de Proteínas Quinases , Pirimidinas , Humanos , Pirimidinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Estrutura-Atividade , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Tiofenos/farmacologia , Tiofenos/síntese química , Tiofenos/química , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Linhagem Celular Tumoral , Descoberta de Drogas , Apoptose/efeitos dos fármacos , Feminino , Camundongos Nus , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C
2.
BMJ Open ; 14(3): e074854, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38471679

RESUMO

OBJECTIVE: To evaluate the quality and analyse the content of clinical practice guidelines regarding central venous catheter-related thrombosis (CRT) to provide evidence for formulating an evidence-based practice protocol and a risk assessment scale to prevent it. DESIGN: Scoring and analysis of the guidelines using the AGREE II and AGREE REX scales. DATA SOURCES: Pubmed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP, and the Chinese Biomedical Literature, and the relevant websites of the guideline, were searched from 1 January 2017 to 26 March 2022. ELIGIBILITY CRITERIA: Guidelines covering CRT treatment, prevention, or management were included from 1 January 2017 to 26 March 2022. DATA EXTRACTION AND SYNTHESIS: Three independent reviewers systematically trained in using the AGREE II and AGREE REX scales were selected to evaluate these guidelines. RESULTS: Nine guidelines were included, and the quality grade results showed that three were at A-level and six were at B-level. The included guidelines mainly recommended the prevention measure of central venous CRT from three aspects: risk screening, prevention strategies, and knowledge training, with a total of 22 suggestions being recommended. CONCLUSION: The overall quality of the guidelines is high, but there are few preventive measures for central venous CRT involved in the guidelines. All preventive measures have yet to be systematically integrated and evaluated, and no risk assessment scale dedicated to this field has been recommended. Therefore, developing an evidence-based practice protocol and a risk assessment scale to prevent it is urgent.


Assuntos
Cateteres Venosos Centrais , Trombose , Humanos , Prática Clínica Baseada em Evidências , Guias de Prática Clínica como Assunto
3.
J Med Chem ; 66(8): 5719-5752, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-37042119

RESUMO

Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for the treatment of non-small-cell lung cancer (NSCLC). Here, we report the identification, structure optimization, and structure-activity relationship studies of quinazoline derivatives as novel selective EGFR L858R/T790M inhibitors. The most promising compound, 28f, exhibited strong inhibitory activity against EGFR L858R/T790M (IC50 = 3.5 nM) and greater than 368-fold selectivity over EGFR WT (IC50 = 1290 nM), a 6.7-fold improvement over osimertinib. Furthermore, 28f effectively inhibited downstream signaling pathways and induced apoptosis in mutant cells. In the H1975 xenograft in vivo model, 28f exhibited a good tumor suppressive effect. Furthermore, the combination of 28f with the ACK1 inhibitor dasatinib produced synergistic antiproliferative efficacy with 28f in 28f-resistant cells and in vivo. In conclusion,28f could become a candidate drug for the treatment of NSCLC, and the combination of 28f and dasatinib is expected to overcome EGFR resistance.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Proliferação de Células , Dasatinibe/farmacologia , Linhagem Celular Tumoral , Mutação , Inibidores de Proteínas Quinases/farmacologia , Resistencia a Medicamentos Antineoplásicos , Antineoplásicos/farmacologia
4.
Transl Neurodegener ; 12(1): 9, 2023 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-36850004

RESUMO

Physical exercise is of great significance for maintaining human health. Exercise can provide varying degrees of benefits to cognitive function at all stages of life cycle. Currently, with the aging of the world's population and increase of life expectancy, cognitive dysfunction has gradually become a disease of high incidence, which is accompanied by neurodegenerative diseases in elderly individuals. Patients often exhibit memory loss, aphasia and weakening of orientation once diagnosed, and are unable to have a normal life. Cognitive dysfunction largely affects the physical and mental health, reduces the quality of life, and causes a great economic burden to the society. At present, most of the interventions are aimed to maintain the current cognitive level and delay deterioration of cognition. In contrast, exercise as a nonpharmacological therapy has great advantages in its nontoxicity, low cost and universal application. The molecular mechanisms underlying the effect of exercise on cognition are complex, and studies have been extensively centered on neural plasticity, the direct target of exercise in the brain. In addition, mitochondrial stability and energy metabolism are essential for brain status. Meanwhile, the organ-brain axis responds to exercise and induces release of cytokines related to cognition. In this review, we summarize the latest evidence on the molecular mechanisms underlying the effects of exercise on cognition, and point out directions for future research.


Assuntos
Disfunção Cognitiva , Qualidade de Vida , Idoso , Humanos , Disfunção Cognitiva/genética , Disfunção Cognitiva/terapia , Cognição , Encéfalo , Envelhecimento
6.
J Med Chem ; 66(2): 1273-1300, 2023 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-36649216

RESUMO

c-Jun N-terminal kinases (JNKs) are involved in the pathogenesis of various diseases. In particular, JNK3 and not JNK1/2 is primarily expressed in the brain and plays a key role in mediating neurodegenerative diseases like Parkinson's disease (PD). Due to the sequence similarity of JNK isoforms, developing isoform-selective JNK3 inhibitors to evaluate their biological functions and therapeutic potential in PD has become a challenge. Herein, docking-based virtual screening and structure-activity relationship studies identified 25c with excellent inhibitory activity against JNK3 (IC50 = 85.21 nM) and exhibited an over 100-fold isoform selectivity for JNK3 over JNK1/2 and remarkable kinase selectivity. 25c showed neuroprotective effects on in vitro and in vivo PD models by selectively inhibiting JNK3. Meanwhile, 25c showed an ideal blood-brain barrier permeability and low toxicity. Overall, this study provided a valuable molecular tool for investigating the role of JNK3 in PD and a solid foundation for developing JNK3-targeted drugs in PD treatment.


Assuntos
Proteína Quinase 10 Ativada por Mitógeno , Doença de Parkinson , Humanos , Indazóis/farmacologia , Indazóis/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Isoformas de Proteínas , Fosforilação , Proteínas Quinases JNK Ativadas por Mitógeno
7.
Acta Pharm Sin B ; 12(5): 2171-2192, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35646548

RESUMO

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is widely activated by a variety of extracellular stimuli, and its dysregulation is associated with the proliferation, invasion, and migration of cancer cells. ERK1/2 is located at the distal end of this pathway and rarely undergoes mutations, making it an attractive target for anticancer drug development. Currently, an increasing number of ERK1/2 inhibitors have been designed and synthesized for antitumor therapy, among which representative compounds have entered clinical trials. When ERK1/2 signal transduction is eliminated, ERK5 may provide a bypass route to rescue proliferation, and weaken the potency of ERK1/2 inhibitors. Therefore, drug research targeting ERK5 or based on the compensatory mechanism of ERK5 for ERK1/2 opens up a new way for oncotherapy. This review provides an overview of the physiological and biological functions of ERKs, focuses on the structure-activity relationships of small molecule inhibitors targeting ERKs, with a view to providing guidance for future drug design and optimization, and discusses the potential therapeutic strategies to overcome drug resistance.

8.
J Med Chem ; 65(5): 3758-3775, 2022 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-35200035

RESUMO

c-Jun N-terminal kinases (JNKs), members of the mitogen-activated protein kinase (MAPK) family, are encoded by three genes: jnk1, jnk2, and jnk3. JNKs are involved in the pathogenesis and development of many diseases, such as neurodegenerative diseases, inflammation, and cancers. Therefore, JNKs have become important therapeutic targets. Many JNK inhibitors have been discovered, and some have been introduced into clinical trials. However, the study of isoform-selective JNK inhibitors is still a challenging task. To further develop novel JNK inhibitors with clinical value, a comprehensive understanding of JNKs and their corresponding inhibitors is required. In this Perspective, we introduced the JNK signaling pathways and reviewed different chemical types of JNK inhibitors, focusing on their structure-activity relationships and biological activities. The challenges and strategies for the development of JNK inhibitors are also discussed. It is hoped that this Perspective will provide valuable references for the development of novel selective JNK inhibitors.


Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno , Neoplasias , Humanos , Sistema de Sinalização das MAP Quinases , Neoplasias/tratamento farmacológico , Fosforilação , Isoformas de Proteínas/metabolismo
9.
Drug Discov Today ; 27(7): 1815-1831, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34808390

RESUMO

Autophagy is a multistep degradation pathway involving the lysosome, which supports nutrient reuse and metabolic balance, and has been implicated as a process that regulates cancer genesis and development. Targeting tumors by regulating autophagy has become a therapeutic strategy of interest. Drugs with other indications can have antitumor activity by modulating autophagy, providing a shortcut to developing novel antitumor drugs (i.e., drug repurposing/repositioning), as successfully performed for chloroquine (CQ); an increasing number of repurposed drugs have since advanced into clinical trials. In this review, we describe the application of different drug-repurposing approaches in autophagy for the treatment of cancer and focus on repurposing drugs that target autophagy to treat malignant neoplasms.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Reposicionamento de Medicamentos , Humanos , Neoplasias/metabolismo
10.
Chem Commun (Camb) ; 57(97): 13194-13197, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34816823

RESUMO

Autophagy-based protein degradation is emerging as a promising technology for anti-diseases and innovative drug discovery. Here, we demonstrate a novel type of autophagy-targeting chimera (AUTAC) to degrade protein by targeting autophagy key protein LC3. The best compound 10f powerfully degraded BRD4 protein through the autophagy pathway and exhibited good anti-proliferative activity in multiple tumor cells, providing a powerful toolbox for medicinal chemists to study disease-related targets with autophagy-based degradation.


Assuntos
Autofagia , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células HeLa , Humanos , Estrutura Molecular , Fatores de Transcrição/metabolismo
11.
J Med Chem ; 64(12): 7963-7990, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34101463

RESUMO

Microtubules play a crucial role in multiple cellular functions including mitosis, cell signaling, and organelle trafficking, which makes the microtubule an important target for cancer therapy. Despite the great successes of microtubule-targeting agents in the clinic, the development of drug resistance and dose-limiting toxicity restrict their clinical efficacy. In recent years, multitarget therapy has been considered an effective strategy to achieve higher therapeutic efficacy, in particular dual-target drugs. In terms of the synergetic effect of tubulin and other antitumor agents such as receptor tyrosine kinases inhibitors, histone deacetylases inhibitors, DNA-damaging agents, and topoisomerase inhibitors in combination therapy, designing dual-target tubulin inhibitors is regarded as a promising approach to overcome these limitations and improve therapeutic efficacy. In this Perspective, we discussed rational target combinations, design strategies, structure-activity relationships, and future directions of dual-target tubulin inhibitors.


Assuntos
Antineoplásicos/farmacologia , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Moduladores de Tubulina/química
12.
Molecules ; 26(4)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33579052

RESUMO

Microtubules composed of α/ß tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure-activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.


Assuntos
Caseína Quinase I/antagonistas & inibidores , Desenho de Fármacos , Indóis/química , Microtúbulos/efeitos dos fármacos , Floroglucinol/análogos & derivados , Tubulina (Proteína)/química , Animais , Sítios de Ligação , Colchicina/química , Colchicina/metabolismo , Cristalografia por Raios X , Indóis/metabolismo , Simulação de Acoplamento Molecular , Floroglucinol/química , Floroglucinol/metabolismo , Conformação Proteica , Relação Estrutura-Atividade , Suínos , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo
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