Intrinsic signaling pathways modulate targeted protein degradation

• Published in: Nature communications 2024-07, Vol.15 (1), p.5379-14, Article 5379
• Main Authors: Mori, Yuki, Akizuki, Yoshino, Honda, Rikuto, Takao, Miyu, Tsuchimoto, Ayaka, Hashimoto, Sota, Iio, Hiroaki, Kato, Masakazu, Kaiho-Soma, Ai, Saeki, Yasushi, Hamazaki, Jun, Murata, Shigeo, Ushijima, Toshikazu, Hattori, Naoko, Ohtake, Fumiaki
• Format: Article
• Language: English
• Subjects: 13/1; 13/89; 631/45/474/582; 631/80/474/2073; 631/92/458/582; 82/58; 82/83; Apoptosis; Apoptosis - drug effects; Biodegradation; Bromodomain Containing Proteins; Cancer; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Chromatin; Cyclin-Dependent Kinase 9 - antagonists & inhibitors; Cyclin-Dependent Kinase 9 - metabolism; Degradation; Drug discovery; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humanities and Social Sciences; Humans; Inhibitors; multidisciplinary; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein folding; Proteins; Proteolysis - drug effects; Regulatory mechanisms (biology); Ribosylation; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Transcription Factors - genetics; Transcription Factors - metabolism; Ubiquitin; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49519-z

Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2 VHL - or CRL4 CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4–PROTAC–CRL2 VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors. Targeted protein degradation harnessing the ubiquitin system is a groundbreaking modality in drug discovery. Here, the authors identify cellular signaling pathways, such as PARG, PERK, or HSP90, that modulate the targeted degradation of the anticancer targets such as BRD4 induced by PROTACs.