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

Abstract

In the version of this article originally published, several lines of text in the last paragraph of the right column on page 1 of the PDF were transposed into the bottom paragraph of the left column. The affected text of the left column should read "The ATP-dependent activities of the BAF (SWI/SNF) chromatin remodeling complexes affect the positioning of nucleosomes on DNA and thereby many cellular processes related to chromatin structure, including transcription, DNA repair and decatenation of chromosomes during mitosis 12,13. " The affected text of the right column should read "SMARCA2/4 BD inhibitors are thus precluded from use for the treatment of SMARCA4 mutant cancers but could provide attractive ligands for PROTAC conjugation. Small molecules binding to other bromodomains have been successfully converted into PROTACs by conjugating them with structures capable of binding to the E3 ligases von Hippel−Lindau (VHL) or cereblon 5,6,10,11,25,26,27. " The errors have been corrected in the PDF version of the paper.

Mechanistic and Structural Features of PROTAC Ternary Complexes

“…As more PROTAC is titrated into the assay, more ternary complexes are formed and a higher intensity signal is received, until the hook effect kicks in. Others have adopted similar approaches to compare other VHL-recruiting degraders, which target other bromodomains such as Brd7/9 [30], and SMARCA2/4 [41], or to analyse CRBN-recruiting BET PRO-TACs [48,49]. TR-FRET assays have been widely used to study ternary complexes formed by monovalent molecular glues such as IMiDs with the E3 ligase CRBN and recruited neo-substrate proteins [8], and more recently small-molecule enhancers of the oncogenic transcriptional factor, β-Catenin and the SCF β-TrCP E3 ligase [50].…”

“…Structural information has also been leveraged to drive the design of potent PROTACs for SMARCA2 and SMARCA4 proteins [41]. These are subunits of chromatin remodelling BAF/PBAF complexes which have been identified as cancer targets [41].…”

“…Structural information has also been leveraged to drive the design of potent PROTACs for SMARCA2 and SMARCA4 proteins [41]. These are subunits of chromatin remodelling BAF/PBAF complexes which have been identified as cancer targets [41]. Although ligands exist for the bromodomains of these proteins, they have been shown to be ineffective as a cancer therapy [42].…”

Recent Advances in PROTACs for Drug Targeted Protein Research

“…The general process is that PROTAC binds the target protein (POI) and E3 ligase to form a ternary complex, marking the target protein with the label of ubiquitination. The ubiquitinated proteins are recognized and degraded by the intracellular 26S proteasome [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ] ( Figure 1 ). The E3 ubiquitin ligase has approximately more than 600 members and is the most diverse component of the ubiquitin–proteasome system.…”

Protein and mRNA Quantification in Small Samples of Human Induced Pluripotent Stem-cell-derived Cardiomyocytes in 96-well Microplates

“…Based on capillary electrophoresis, the Wes TM ProteinSimple platform for protein quantification was commercialized and has demonstrated high sensitivity, wide dynamic range and good reproducibility (21)(22)(23). Since deployment, it has been widely used in cancer (24,25) and neuroscience (26,27), with some recent applications to cardiac research (28)(29)(30)(31)(32)(33)(34). The key advantages of this system over standard WB include the small starting material needed (as low as 0.8µg per sample), the level of automation and high throughput (runs up to 24 samples concurrently) and faster turnover (3-5 hours assay time), all of which make it ideal for applications requiring analysis of many protein samples limited by size.…”