BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design

Abstract

Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here we develop PROTAC degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization towards ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced antiproliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets and pave the way towards new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.

Deep Generative Models for 3D Compound Design

“…Finally, we showed the applicability of our method in three diverse examples from the literature, covering fragment linking, 40 scaffold hopping, 41 and PROTAC design. 42 Due to the availability of independent experimental structural data for both the initial and optimised complexes, this represents the most realistic evaluation, albeit with a limited sample size.…”

“…PROTAC case study. Farnaby et al 42 developed PROTAC degraders of the BAF AT- Pase subunits SMARCA2 (UniProt: P51531) and SMARCA4 (UniProt: P51532) using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL (UniProt: P40337). They first designed a PROTAC by combining known binders of SMARCA2/4 and E3 ubiquitin ligase VHL using polyethylene glycol-based linkers (PDB ID: 6HAY, Figure 7a).…”

Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling

“…Heterobifunctional degraders have garnered attention recently due to potential advantages over traditional small molecule inhibitors, including their ability to target proteins deemed undruggable through the use of non-functional ligands (Farnaby et al, 2019;Silva et al, 2019) and to achieve selectivity with promiscuous ligands . However, one advantage of degraders that has not been fully investigated is their potential to exert long-lasting pharmacological effects.…”

Native mass spectrometry can effectively predict PROTAC efficacy

“…1a), is an emerging strategy in drug discovery, having major advantages over traditional small molecule inhibitors.PROTACs eliminate a target protein rather than inhibit it and function in a catalytic manner, requiring sub-stoichiometric amounts to achieve efficiency [4]. Moreover, PROTACs are applicable to a wider spectrum of proteins since degradation is not limited to a specific functional domain or active site [5]. To date, protein degraders have been developed against a variety of medically relevant proteins, such as the tumorigenic Androgen Receptor and Estrogen Receptor, as explored in first clinical trials [5][6][7][8][9][10].…”

“…Moreover, PROTACs are applicable to a wider spectrum of proteins since degradation is not limited to a specific functional domain or active site [5]. To date, protein degraders have been developed against a variety of medically relevant proteins, such as the tumorigenic Androgen Receptor and Estrogen Receptor, as explored in first clinical trials [5][6][7][8][9][10]. In order to realise the full potential…”