Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
J Enzyme Inhib Med Chem ; 35(1): 1840-1853, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33040634

RESUMO

Haspin is a mitotic protein kinase required for proper cell division by modulating Aurora B kinase localisation and activity as well as histone phosphorylation. Here a series of imidazopyridazines based on the CHR-6494 and Structure Activity Relationship was established. An assessment of the inhibitory activity of the lead structures on human Haspin and several other protein kinases is presented. The lead structure was rapidly optimised using a combination of crystal structures and effective docking models, with the best inhibitors exhibiting potent inhibitory activity on Haspin with IC50 between 6 and 100 nM in vitro. The developed inhibitors displayed anti-proliferative properties against various human cancer cell lines in 2D and spheroid cultures and significantly inhibited the migration ability of osteosarcoma U-2 OS cells. Notably, we show that our lead compounds are powerful Haspin inhibitors in human cells, and did not block G2/M cell cycle transition due to improved selectivity against CDK1/CyclinB.


Assuntos
Antineoplásicos/síntese química , Neoplasias Ósseas/tratamento farmacológico , Indazóis/síntese química , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Osteossarcoma/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridazinas/síntese química , Sequência de Aminoácidos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina B/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Histonas/química , Humanos , Indazóis/farmacologia , Simulação de Acoplamento Molecular , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Relação Estrutura-Atividade
2.
Molecules ; 25(14)2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679723

RESUMO

Since the first approval of a protein kinase inhibitor (PKI) by the Food and Drug Administration (FDA) in 2001, 55 new PKIs have reached the market, and many inhibitors are currently being evaluated in clinical trials. This is a clear indication that protein kinases still represent major drug targets for the pharmaceutical industry. In a previous work, we have introduced PKIDB, a publicly available database, gathering PKIs that have already been approved (Phase 4), as well as those currently in clinical trials (Phases 0 to 3). This database is updated frequently, and an analysis of the new data is presented here. In addition, we compared the set of PKIs present in PKIDB with the PKIs in early preclinical studies found in ChEMBL, the largest publicly available chemical database. For each dataset, the distribution of physicochemical descriptors related to drug-likeness is presented. From these results, updated guidelines to prioritize compounds for targeting protein kinases are proposed. The results of a principal component analysis (PCA) show that the PKIDB dataset is fully encompassed within all PKIs found in the public database. This observation is reinforced by a principal moments of inertia (PMI) analysis of all molecules. Interestingly, we notice that PKIs in clinical trials tend to explore new 3D chemical space. While a great majority of PKIs is located on the area of "flatland", we find few compounds exploring the 3D structural space. Finally, a scaffold diversity analysis of the two datasets, based on frequency counts was performed. The results give insight into the chemical space of PKIs, and can guide researchers to reach out new unexplored areas. PKIDB is freely accessible from the following website: http://www.icoa.fr/pkidb.


Assuntos
Bases de Dados Factuais , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Fenômenos Químicos , Bases de Dados de Compostos Químicos , Aprovação de Drogas , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
3.
Molecules ; 23(4)2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29662024

RESUMO

The number of protein kinase inhibitors (PKIs) approved worldwide continues to grow steadily, with 39 drugs approved in the period between 2001 and January 2018. PKIs on the market have been the subject of many reviews, and structure-property relationships specific to this class of drugs have been inferred. However, the large number of PKIs under development is often overlooked. In this paper, we present PKIDB (Protein Kinase Inhibitor Database), a monthly-updated database gathering approved PKIs as well as PKIs currently in clinical trials. The database compiles currently 180 inhibitors ranging from phase 0 to 4 clinical trials along with annotations extracted from seven public resources. The distribution and property ranges of standard physicochemical properties are presented. They can be used as filters to better prioritize compound selection for future screening campaigns. Interestingly, more than one-third of the kinase inhibitors violate at least one Lipinski's rule. A Principal Component Analysis (PCA) reveals that Type-II inhibitors are mapped to a distinct chemical space as compared to orally administrated drugs as well as to other types of kinase inhibitors. Using a Principal Moment of Inertia (PMI) analysis, we show that PKIs under development tend to explore new shape territories as compared to approved PKIs. In order to facilitate the analysis of the protein space, the kinome tree has been annotated with all protein kinases being targeted by PKIs. Finally, we analyzed the pipeline of the pharmaceutical companies having PKIs on the market or still under development. We hope that this work will assist researchers in the kinase field in identifying and designing the next generation of kinase inhibitors for still untargeted kinases. The PKIDB database is freely accessible from a website at http://www.icoa.fr/pkidb and can be easily browsed through a user-friendly spreadsheet-like interface.


Assuntos
Ensaios Clínicos como Assunto , Bases de Dados como Assunto , Inibidores de Proteínas Quinases/farmacologia , Sítios de Ligação , Aprovação de Drogas , Modelos Moleculares , Análise de Componente Principal
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA