Development of a Bestatin-SAHA Hybrid with Dual Inhibitory Activity against APN and HDAC.

Jiangying Cao,Shunda Li,Wei Zhao,C James Chou,Qian Liu,Guozhen Zhang,Chunlong Zhao,Yingjie Zhang

doi:10.3390/molecules25214991

Abstract

With five histone deacetylase (HDAC) inhibitors approved for cancer treatment, proteolysis-targeting chimeras (PROTACs) for degradation of HDAC are emerging as an alternative strategy for HDAC-targeted therapeutic intervention. Herein, three bestatin-based hydroxamic acids (P1, P2 and P3) were designed, synthesized and biologically evaluated to see if they could work as HDAC degrader by recruiting cellular inhibitor of apoptosis protein 1 (cIAP1) E3 ubiquitin ligase. Among the three compounds, the bestatin-SAHA hybrid P1 exhibited comparable even more potent inhibitory activity against HDAC1, HDAC6 and HDAC8 relative to the approved HDAC inhibitor SAHA. It is worth noting that although P1 could not lead to intracellular HDAC degradation after 6 h of treatment, it could dramatically decrease the intracellular levels of HDAC1, HDAC6 and HDAC8 after 24 h of treatment. Intriguingly, the similar phenomenon was also observed in the HDAC inhibitor SAHA. Cotreatment with proteasome inhibitor bortezomib could not reverse the HDAC decreasing effects of P1 and SAHA, confirming that their HDAC decreasing effects were not due to protein degradation. Moreover, all three bestatin-based hydroxamic acids P1, P2 and P3 exhibited more potent aminopeptidase N (APN, CD13) inhibitory activities than the approved APN inhibitor bestatin, which translated to their superior anti-angiogenic activities. Taken together, a novel bestatin-SAHA hybrid was developed, which worked as a potent APN and HDAC dual inhibitor instead of a PROTAC.

Highlights

Histone deacetylases (HDACs) can catalyze the removal of acetyl group from lysine residues of histones or some non-histone proteins, playing an essential role in the regulation of gene expression and protein function [1]
In the aspect of biological function, proteolysis-targeting chimeras (PROTACs) can bring the protein of interest and E3-ligase to be adjacent to each other, E3-ligase facilitates the transfer of ubiquitin to the target protein, leading to the degradation of the ubiquitinated target protein by proteasome [6,7,8,9]
The synthesis of target compound P1 was described in Scheme 1

Summary

Introduction

Histone deacetylases (HDACs) can catalyze the removal of acetyl group from lysine residues of histones or some non-histone proteins, playing an essential role in the regulation of gene expression and protein function [1]. An alternative strategy for inhibiting the biological function of proteins is promoting degradation of the target proteins, such as proteolysis-targeting chimeras (PROTACs), a newly developed technique to knockdown the proteins of interest using the cellular ubiquitin-proteasome system [6,7,8,9]. In the aspect of biological function, PROTACs can bring the protein of interest and E3-ligase to be adjacent to each other, E3-ligase facilitates the transfer of ubiquitin to the target protein, leading to the degradation of the ubiquitinated target protein by proteasome [6,7,8,9]. In the research field of PROTACs for HDAC degradation, several effective degraders recruiting CRBN (compounds 1, 2, 3 and 4) or VHL (compounds 5 and 6) have already been successfully developed, among which PROTACs 1–5 are all HDAC6 degraders, while PROTAC 6 can effectively degrade HDAC1, HDAC2 and HDAC3 (Figure 1) [10,11,12,13,14,15]

Methods

Results

Conclusion