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1.
J Med Chem ; 67(8): 6099-6118, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38586950

RESUMO

The duality of function (cell cycle regulation and gene transcription) of cyclin-dependent kinase 7 (CDK7) makes it an attractive oncology target and the discovery of CDK7 inhibitors has been a long-term pursuit by academia and pharmaceutical companies. However, achieving selective leading compounds is still difficult owing to the similarities among the ATP binding pocket. Herein, we detail the design and synthesis of a series of macrocyclic derivatives with pyrazolo[1,5-a]-1,3,5-triazine core structure as potent and selective CDK7 inhibitors. The diverse manners of macrocyclization led to distinguished selectivity profiles of the CDK family. Molecular dynamics (MD) simulation explained the binding difference between 15- and 16-membered macrocyclic compounds. Further optimization generated compound 37 exhibiting good CDK7 inhibitory activity and high selectivity over other CDKs. This work clearly demonstrated macrocyclization is a versatile method to finely tune the selectivity profile of small molecules and MD simulation can be a valuable tool in prioritizing designs of the macrocycle.


Assuntos
Quinases Ciclina-Dependentes , Desenho de Fármacos , Compostos Macrocíclicos , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinase Ativadora de Quinase Dependente de Ciclina
2.
Bioorg Med Chem Lett ; 101: 129658, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38373466

RESUMO

Bcl-2 anti-apoptotic protein family suppresses cell death by deploying a surface groove to capture the critical BH3 α-helix of pro-apoptotic members. Bfl-1 is a relatively understudied member of this family, though it has been implicated in the pathogenesis and chemoresistance of a variety of human cancers. Reported small molecular Bfl-1 inhibitors encountered the issue of either lack in potency or poor selectivity against its most homologous member Mcl-1. In order to tackle this issue, compound library was screened and a hit compound UMI-77 was identified. We modified its chemical structure to remove the characteristic of PAINS (pan-assay interference compounds), demonstrated the real binding affinity and achieved selectivity against Mcl-1 under the guidance of computational modeling. After optimization 15 was obtained as leading compound to block Bfl-1/BIM interaction in vitro with more than 10-fold selectivity over Mcl-1. We believe 15 is of great value for the exploration of Bfl-1 biological function and its potential as therapeutic target.


Assuntos
Neoplasias , Proteínas Proto-Oncogênicas c-bcl-2 , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides , Ácido Acético , Proteínas Reguladoras de Apoptose , Neoplasias/metabolismo , Apoptose
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