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Effect of PDD00017273 and GSK2606414 on MZ1-induced cell death

ABSTRACT: Targeted protein degradation is a groundbreaking modality in drug discovery ; however, further improvement of the degradation efficacy is demanded. Here, we identify small molecules that enhance the targeted degradation of the anticancer target BRD4 and related hard-to-degrade targets BRD2/3 induced by CRL2VHL- or CRL4CRBN -based PROTACs. The chemicals 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– CRL2VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. Combining the treatment with these chemicals further increases the efficacy of a highly potent PROTAC, SIM1. We propose that various cell intrinsic signaling pathways spontaneously counteract chemically induced target degradation, which can be liberated by specific inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243615 | GEO | 2024/05/17

REPOSITORIES: GEO

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ChIP-seq of BRD4 of HCT116 cells treated with MZ1 or PDD00017273

Project description: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 hard-to-degrade targets BRD2/3 induced by CRL2VHL- or CRL4CRBN -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–CRL2VHL 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.

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