RESUMO
A major goal of medicinal chemists is to identify and validate novel and effective kinase targets for treatment of cancer. Recent studies have shown that cyclin-dependent kinase 8 (CDK8) is a target for treatment of colorectal, breast, melanoma, and prostate cancers. The crystal structure of CDK8 has been reported, and eutectic interactions have been identified for 24 compounds that target CDK8. To more effectively develop CDK8 inhibitors, particularly those with improved selectivity, we summarized the structure, structure-activity relationships, and binding information of typical CDK8 inhibitors, which may serve as a reference for development of novel CDK8 inhibitors.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Quinase 8 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Quinase 8 Dependente de Ciclina/química , Quinase 8 Dependente de Ciclina/metabolismo , Descoberta de Drogas , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/metabolismo , Relação Estrutura-AtividadeRESUMO
Basis on molecular docking and pharmacophore analysis of naphthoquinone moiety, a total of 23 compounds were designed and synthesised. With the help of reverse targets searching, anti-cancer activity was preliminarily evaluated, most of them are effective against some tumour cells, especially compound 12: 1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl-4-oxo-4-((4-phenoxyphenyl)amino) butanoate whose IC50 against SGC-7901 was 4.1 ± 2.6 µM. Meanwhile the anticancer mechanism of compound 12 had been investigated by AnnexinV/PI staining, immunofluorescence, Western blot assay and molecular docking. The results indicated that this compound might induce cell apoptosis and cell autophagy through regulating the PI3K signal pathway.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Naftoquinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
CDK8 is a transcriptional cyclin-dependent kinase and considered as a potential target in colon cancer therapeutics. Here, a novel selective CDK8 inhibitor was identified against colon cancer in vivo. Specifically, based on the structural information of the sorafenib-bound CDK8 structure, a series of novel 2-amino-pyridine derivatives were designed, synthesized, and evaluated. Among them, compound 29 showed strong inhibitory activity against CDK8 with an IC50 value of 46 nM and favorable selectivity. And there is an apparent interaction between the endogenous or overexpressed CDK8 and biotinylated-29. This compound exhibited antiproliferation potency on colon cancer cell lines with a high CDK8 expression level, suppressed the activation of WNT/ß-catenin and transcriptional activity of the TCF family, and induced G1 phase arrested in HCT-116 cells. In addition, this compound showed potent activity against sorafenib-resistant HCT-116 cells. What's more, it exhibited low toxicity and suitable pharmacokinetic (PK) profiles and showed preferable antitumor effects in vivo.
Assuntos
Neoplasias do Colo , beta Catenina , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Quinase 8 Dependente de Ciclina , Quinases Ciclina-Dependentes/metabolismo , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe , beta Catenina/metabolismoRESUMO
Cathepsin C, an important lysosomal cysteine protease, mediates the maturation process of neutrophil serine proteases, and participates in the inflammation and immune regulation process associated with polymorphonuclear neutrophils. Therefore, cathepsin C is considered to be an attractive target for treating inflammatory diseases. With INS1007 (trade name: brensocatib) being granted a breakthrough drug designation by FDA for the treatment of Adult Non-cystic Fibrosis Bronchiectasis and Coronavirus Disease 2019, the development of cathepsin C inhibitor will attract attentions from medicinal chemists in the future soon. Here, we summarized the research results of cathepsin C as a therapeutic target, focusing on the development of cathepsin C inhibitor, and provided guidance and reference opinions for the upcoming development boom of cathepsin C inhibitor.
Assuntos
Anti-Inflamatórios/química , Catepsina C/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteases/química , Anti-Inflamatórios/uso terapêutico , COVID-19/patologia , COVID-19/virologia , Catepsina C/genética , Catepsina C/metabolismo , Humanos , Doença de Papillon-Lefevre/genética , Doença de Papillon-Lefevre/patologia , Inibidores de Proteases/metabolismo , Inibidores de Proteases/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/patologia , SARS-CoV-2/isolamento & purificação , Serina Endopeptidases/metabolismo , Tratamento Farmacológico da COVID-19RESUMO
Eleven dihydroxy-2-(1-hydroxy-4-methylpent-3-enyl)naphthalene derivatives as anticancer agents through regulating cell autophagy were designed and synthesized. The anticancer activity results indicated that most compounds manifested obvious un-toxic effect on GES-1 and L-02 with IC50 from 0.58 to 1.41 mM. Among them, (S,Z)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 4-(3,4- dihydroisoquinolin-2(1 H)-yl)-4-oxobut-2-enoate (compound 4i) could induce cancer cells apoptosis. Further experiments showed that autophagy played an important role in the pro-apoptotic effect of this compound. Preliminary mechanism indicated that this compound could inhibit phosphoinositide 3-kinase/protein kinase B and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway by mediating apoptosis in an autophagy-dependent manner.
Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Naftalenos/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Naftalenos/síntese química , Naftalenos/química , Neoplasias/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismoRESUMO
The direct C-H bond arylation of (benzo)oxazoles with aryl chlorides was achieved catalyzed by a well-defined NHC-Pd(II)-Im complex. Under the optimal conditions, various aryl chlorides were successfully applied as the arylating reagents to achieve the 2-aryl (benzo)oxazoles in acceptable to high yields, providing a convenient and alternative method for the direct C-H bond arylation of (benzo)oxazoles and enriching the chemistry of the NHC-Pd(II) complex in organic synthesis.