Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer

Author(s):  
Zhuoxian Cao ◽  
Fenfen Yang ◽  
Jie Wang ◽  
Zhicheng Gu ◽  
Shuxian Lin ◽  
...  
2021 ◽  
Vol 28 ◽  
Author(s):  
Davide Bonanni ◽  
Andrea Citarella ◽  
Davide Moi ◽  
Luca Pinzi ◽  
Elisa Bergamini ◽  
...  

: The design of multi-target drugs acting simultaneously on multiple signaling pathways is a growing field in medicinal chemistry, especially for the treatment of complex diseases such as cancer. Histone deacetylase 6 (HDAC6) is an established anticancer drug target involved in tumor cells transformation. Being an epigenetic enzyme at the interplay of many biological processes, HDAC6 has become an attractive target for polypharmacology studies aimed at improving therapeutic efficacy of anticancer drugs. For example, the molecular chaperone Heat shock protein 90 (Hsp90) is a substrate of HDAC6 deacetylation, and several lines of evidence demonstrate that simultaneous inhibition of HDAC6 and Hsp90 promote synergistic antitumor effects on different cancer cell lines, highlighting the potential benefits of developing a single molecule endowed with multi-target activity. This review will summarize the complex interplay between HDAC6 and Hsp90, providing also useful hints for multi-target drug design and discovery approaches in this field. To this end, crystallographic structures of HDAC6 and Hsp90 complexes will be extensively reviewed in the light of discussing binding pockets features and pharmacophore requirements and providing useful guidelines for the design of dual inhibitors. The few examples of multi-target inhibitors obtained so far, mostly based on chimeric approaches, will be summarized and put into context. Finally, the main features of HDAC6 and Hsp90 inhibitors will be compared, and ligand- and structure-based strategies potentially useful for the development of small molecular weight dual inhibitors will be proposed and discussed.


ACS Omega ◽  
2020 ◽  
Vol 5 (20) ◽  
pp. 11473-11480 ◽  
Author(s):  
Luca Pinzi ◽  
Rosaria Benedetti ◽  
Lucia Altucci ◽  
Giulio Rastelli

2020 ◽  
Vol 94 ◽  
pp. 103409 ◽  
Author(s):  
Gaurav Joshi ◽  
Sourav Kalra ◽  
Umesh Prasad Yadav ◽  
Praveen Sharma ◽  
Pankaj Kumar Singh ◽  
...  

RSC Advances ◽  
2016 ◽  
Vol 6 (105) ◽  
pp. 103178-103184 ◽  
Author(s):  
Xin Chen ◽  
Shuang Zhao ◽  
Yichao Wu ◽  
Yadong Chen ◽  
Tao Lu ◽  
...  

A novel design approach: combination of Bcr-Abl and HDAC inhibitory activity in one molecule to produce dual inhibitors.


RSC Advances ◽  
2017 ◽  
Vol 7 (82) ◽  
pp. 52180-52186 ◽  
Author(s):  
Yichao Wu ◽  
Weichen Dai ◽  
Xin Chen ◽  
Aixin Geng ◽  
Yadong Chen ◽  
...  

A novel design approach by combination of PI3K and HDAC inhibitory activity in one molecule to produce dual inhibitors.


2013 ◽  
Vol 21 (22) ◽  
pp. 6981-6995 ◽  
Author(s):  
Xuan Zhang ◽  
Bin Bao ◽  
Xiuhua Yu ◽  
Linjiang Tong ◽  
Yu Luo ◽  
...  

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