RESUMEN
The B-cell lymphoma-2 (Bcl-2) family proteins are attractive targets for cancer therapy. In our previous work, the structure-activity relationship of WL-276 was studied. According to the results, rhodanine derivatives show potent binding affinity for Bcl-2 and Mcl-1 protein and show weaker activity against Bcl-XL protein. Based on the previous results, a new class of indole-3-carboxylic acid-based derivatives were designed and synthesized as Bcl-2/Mcl-1 dual inhibitors. Among them, compound 17 has a Ki value of 0.26µM for Bcl-2 protein and is better than WL-276. Furthermore, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a Ki value of 72nM. Especially, compound 31 can selectively acting on Bcl-2 and Mcl-1 protein but not Bcl-XL protein, which has great significance for developing dual inhibitors targeting Bcl-2 and Mcl-1 protein, as well as specific antitumor abilities in cells.
Asunto(s)
Diseño de Fármacos , Indoles/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Espectroscopía de Resonancia Magnética con Carbono-13 , Evaluación Preclínica de Medicamentos , Polarización de Fluorescencia , Humanos , Indoles/química , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
As key regulators of epigenetic regulation, human histone deacetylases (HDACs) have been identified as drug targets for the treatment of several cancers. The proper recognition of zinc-binding groups (ZBGs) will help improve the accuracy of virtual screening for novel HDAC inhibitors. Here, we developed a high-specificity ZBG-based pharmacophore model for HDAC8 inhibitors by incorporating customized ZBG features. Subsequently, pharmacophore-based virtual screening led to the discovery of three novel HDAC8 inhibitors with low micromole IC50 values (1.8-1.9 µM). Further studies demonstrated that compound H8-A5 was selective for HDAC8 over HDAC 1/4 and showed antiproliferation activity in MDA-MB-231 cancer cells. Molecular docking and molecular dynamic studies suggested a possible binding mode for H8-A5, which provides a good starting point for the development of HDAC8 inhibitors in cancer treatment.