# Design and synthesis of novel HDAC6 inhibitor dimer as HDAC6 degrader for cancer treatment by palladium catalysed dimerisation

## TL;DR

This paper presents a new method to create HDAC6 inhibitor dimers that effectively treat cancer by inhibiting HDAC6 and inducing its degradation.

## Contribution

A novel palladium-catalyzed dimerization method for creating HDAC6 degraders with enhanced biological activity.

## Key findings

- HDAC6 inhibitor dimers show strong inhibition activity (3.9–15.4 nM) and good selectivity.
- Dimers induce HDAC6 degradation and exhibit excellent cytotoxicity against HRPC and NSCLC cell lines.
- Dimers interfere with kinetochore attachment by affecting BUBR1 phosphorylation.

## Abstract

The enigmatic histone deacetylase 6 (HDAC6) is one of a kind among its family. Recent reports revealed that HDAC6 CD1 exhibits E3 ligase activity. Inspired by these researches, we attempted to develop drugs targeting HDAC6 via novel mechanism. Herein, we report a palladium catalysed transformation and purification method for hydroxamic acid dimers, and series of HDAC6 inhibitor-based dimer showing outstanding biological activities and capability of inducing auto-degradation. Our proof-of-concept was highlighted with 2-amino benzamide-based HDAC6 inhibitor dimers that exhibit great HDAC6 inhibition activity (3.9–15.4 nM), good HDAC1/6 selectivity (95–577), and excellent cytotoxicity against human hormone-resistant prostate cancer (HRPC) PC-3 and non-small cell lung cancer (NSCLC) A549 cell lines (5.9–11.3 and 6.6–17.9 μM, respectively) while simultaneously inducing HDAC6 degradation. These dimers not only induce apoptosis and autophagy but also interfere with kinetochore attachment by the detection of BUBR1 phosphorylation at S670.