Design and synthesis of novel cyclin-dependent kinase 4/6(CDK4/6) and histone deacetylase (HDAC) dual inhibitors: In vitro and in vivo anticancer activity
Bongsu Kim , Chandra kantha , Wonku Kang , Jayaprakash Neerasa , Hunsuk Chung
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引用次数: 0
Abstract
Resistance to CDK4/6 inhibitors in certain tumors arises from the upregulation of cyclin D1 and the downregulation of the cell cycle regulator p21. Conversely, HDAC inhibitors can counteract this resistance by upregulating acetyl-histone H3 and p21 expression levels. To address this challenge, we developed a series of novel dual-targeting inhibitors that simultaneously inhibit CDK4/6 and HDAC1. Among these, selected compounds MFDCH016, MFDCH022 and MFDCH025 potently inhibited CDK4 and HDAC1/6 at nM levels, inducing apoptosis and cell cycle arrest in G2/M and G0/G1 phase and promote apoptosis in MCF-7 cells. This effect was mediated through the modulation of the HDAC-p21-CDK signalling pathway, as evidenced by increased acetyl-H3 and p21 levels. Compound MFDCH016 demonstrated significant anti-tumor activity in breast cancer cell line and in MCF-7 xenograft model without apparent toxicity. More importantly MFDCH016 show highly selective against CDK4 over CDK2 compare to standard drug Palbociclib. Our data demonstrated that compound MFDCH016 as a single agent could be novel dual-targeting CDK4/6-HDAC inhibitor could be a promising drug candidate for cancer therapy.
期刊介绍:
The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers.
A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.