Design, Synthesis, and Biological Evaluation of HDAC Degraders with CRBN E3 Ligase Ligands.

Yingxin Lu,Yubo Zhou,Mingbo Su,Donghuai Xiao,Jia Li,Wei Lu,Shulei Zhu,Danwen Sun,Yingying Shao

doi:10.3390/molecules26237241

Abstract

Histone deacetylases (HDACs) play important roles in cell growth, cell differentiation, cell apoptosis, and many other cellular processes. The inhibition of different classes of HDACs has been shown to be closely related to the therapy of cancers and other diseases. In this study, a series of novel CRBN-recruiting HDAC PROTACs were designed and synthesized by linking hydroxamic acid and benzamide with lenalidomide, pomalidomide, and CC-220 through linkers of different lengths and types. One of these PROTACs, denoted 21a, with a new benzyl alcohol linker, exhibited comparably excellent HDAC inhibition activity on different HDAC classes, acceptable degradative activity, and even better in vitro anti-proliferative activities on the MM.1S cell line compared with SAHA. Moreover, we report for the first time the benzyl alcohol linker, which could also offer the potential to be used to develop more types of potent PROTACs for targeting more proteins of interest (POI).

Highlights

Histone deacetylases (HDACs) have been identified as a superfamily of enzymes serving as “epigenetic erasers” [1,2]
We report for the first time the benzyl alcohol linkage between the four-position of lenalidomide or pomalidomide and the “warhead”, which can be used in other types of proteolysis-targeting chimera (PROTAC) (Figure 3C)
With lenalidomide (5a) and pomalidomide (5b) as the CRBN ligands, the key intermediates (6a–6e) with varying linker lengths were obtained through an amide reaction followed by the deprotection of the benzyl group using palladium on carbon (Pd/C) in a hydrogen atmosphere with high yields

Summary

Introduction

Histone deacetylases (HDACs) have been identified as a superfamily of enzymes serving as “epigenetic erasers” [1,2] They play important roles in altering the gene transcription and drug resistance mechanisms of tumor cells due to their ability to remove the acetyl moiety from histone tails [3,4]. Hundreds of hydroxamic acid- and benzamide-type HDACi have been submitted to clinical trials (Figure 1), such as vorinostat (SAHA), panobinostat, belinostat, and chidamide [12,13,14]. These drugs exhibit limited selectivity, which has been attributed as a cause of their debilitating side effects in patients [12,15]. It is urgent to develop an approach to enhance selective HDAC binding

Methods

Results

Discussion

Conclusion