# Unveiling New Triazoloquinoxaline‐Based PROTACs Designed for the Selective Degradation of the ncBAF Chromatin Remodeling Subunit BRD9

## TL;DR

This paper introduces new molecules that can selectively destroy a protein called BRD9, which is linked to cancer, and shows they work well in leukemia cells.

## Contribution

The study presents novel BRD9-targeting PROTACs with a unique chemical scaffold and E3 ligase ligands.

## Key findings

- Two VHL-based PROTACs (2 and 9) effectively degrade BRD9 and show antiproliferative activity in AML cells.
- Compound 9 selectively degrades BRD9 over BRD7, indicating high specificity.
- The new degraders expand the range of molecules available for BRD9-targeted protein degradation.

## Abstract

PROteolysis Targeting Chimera (PROTAC) technology is an innovative and potent approach for achieving targeted protein degradation (TPD). Within bromodomain‐containing proteins, various degraders targeting BET family‐related targets, for example, BRD4, were developed in the last years. On the other hand, a limited number of PROTACs acting against non‐BET proteins were reported so far. Among them, BRD9 was recently linked to oncogenic roles in the tumorigenesis processes, especially in sarcomas and leukemias. Herein, we describe the design and synthesis of a focused collection of new BRD9‐targeting degraders based on the [1,2,4]triazolo[4,3‐a]quinoxaline heterocyclic scaffold employing two distinct E3 ubiquitin ligase ligands. Through in silico evaluation, synthesis, binding affinity determination, and in vitro analysis, we identified two new VHL‐based PROTACs (2 and 9), which showed remarkable degradation of the protein of interest and antiproliferative activity in acute myeloid leukemia (AML) cells. Notably, compound 9 exhibited selective degradation of BRD9 over BRD7. These results enlarge and differentiate the pool of heterobifunctional molecules able to degrade BRD9 through the proteasome machinery, providing a promising reference for the discovery of new tools to further explore both the involvement of this epigenetic regulatory factor in tumor processes and to evaluate novel strategies for AML treatment.

We present new BRD9‐targeting degraders featuring a chemical warhead and E3 ligase ligand that distinctly differ from the typical chemical units used for BRD9 degradation. Specifically, we identified two VHL‐based PROTACs (2 and 9) based on a [1,2,4]triazolo[4,3‐a]quinoxaline scaffold that effectively and selectively degrade BRD9 and exhibit antiproliferative effects in acute myeloid leukemia (AML) cells, offering potential strategies for AML treatment and insights into BRD9's role in tumors.