Abstract 5780: Simultaneous targeting existing proteins and nascent proteins for synergistic anticancer activity

Abstract

Abstract Protein synthesis and subsequent delivery to the target locations in cells are essential for their proper functions. Newly synthesized proteins and existing protein have differential properties that can potentially be exploited for targeting to maximize therapeutic potentials. Methods to label and distinguish newly synthesized proteins from existing ones are critical to assess their differential properties, but such methods are lacking. We describe the first chemical genetics-based approach for selective labeling of existing and newly synthesized proteins that we termed as CG-SLENP. Using HaloTag in-frame fusion with lamin A (LA), we demonstrate that the two pools of proteins can be selectively labeled using CG-SLENP in living cells (https://doi.org/10.1101/2023.11.02.565346). We further employ our recently developed selective small molecule ligand LBL1 for LA to probe the potential differences between newly synthesized and existing LA. Our results show that LBL1 can differentially modulate these two pools of LA. We further extend our CG-SLENP strategy to evaluate the differences of the two pools for BRD4 (bromodomain containing 4). These observed differences motivated us to investigate the synergistic anticancer properties of BRD4 degraders and inhibitors in triple negative breast cancer. Our results show that simultaneous targeting newly synthesized proteins and existing proteins display strong synergistic anticancer activities. Citation Format: Bingbing X. Li, Jian Wang, Bo Chao, Jake Piesner, Felice Kelly, Stefanie Kaech Petrie, Xiangshu Xiao. Simultaneous targeting existing proteins and nascent proteins for synergistic anticancer activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5780.