Cellular Resistance Mechanisms to Targeted Protein Degradation Converge Toward Impairment of the Engaged Ubiquitin Transfer Pathway

Ottis, Philipp; Palladino, Chiara; Thienger, Phillip; Britschgi, Adrian; Heichinger, Christian; Berrera, Marco; Julien-Laferrière, Alice; Roudnicky, Filip; Kam‐Thong, Tony; Bischoff, James R.; Martoglio, Bruno; Pettazzoni, Piergiorgio

doi:10.1021/acschembio.9b00525

Cited by 94 publications

(100 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, resistance to VHL-based BET-PROTACs was found to occur by cullin-2 (CUL2) loss of function due to several genomic alterations in the CUL2 locus, including exon 12 skipping or frameshift mutations which gave rise to a premature stop codon [ 78 ]. Similar findings were also observed by Ottis et al [ 79 ]. Using RNAi of components of the ubiquitin-proteasome system in cells made resistant to BET-PROTACs confirmed that down-regulation or loss of those proteins may lead to PROTAC resistance [ 79 ].…”

Section: Exploiting the Use Of Protacs In The Clinical Settingsupporting

confidence: 92%

“…Similar findings were also observed by Ottis et al [ 79 ]. Using RNAi of components of the ubiquitin-proteasome system in cells made resistant to BET-PROTACs confirmed that down-regulation or loss of those proteins may lead to PROTAC resistance [ 79 ]. Those authors also identified the COP9 signalosome as implicated in the function of BET-PROTACs.…”

Section: Exploiting the Use Of Protacs In The Clinical Settingsupporting

confidence: 92%

See 1 more Smart Citation

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Ocaña

Pandiella

2020

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Exploitation of the protein degradation machinery as a therapeutic strategy to degrade oncogenic proteins is experiencing revolutionary advances with the development of proteolysis targeting chimeras (PROTACs). PROTACs are heterobifunctional structures consisting of a ligand that binds a protein to be degraded and a ligand for an E3 ubiquitin ligase. The bridging between the protein of interest and the E3 ligase mediated by the PROTAC facilitates ubiquitination of the protein and its proteasomal degradation. In this review we discuss the molecular medicine behind PROTAC mechanism of action, with special emphasis on recent developments and their potential translation to the clinical setting.

show abstract

Section: Exploiting the Use Of Protacs In The Clinical Settingsupporting

confidence: 92%

Section: Exploiting the Use Of Protacs In The Clinical Settingsupporting

confidence: 92%

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Ocaña

Pandiella

2020

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…Thus, we cannot rule out at this moment that the degradation observed here may be due to one (or more) other cullin-family E3 ligases that are targeted by CDDO-JQ1. Emerging evidence suggests that clinical resistance to PROTACs can occur through rewiring of the cellular E3 ligase machinery 57,58 , thus highlighting the critical need for more and diverse E3 ligase recruiters. Our combined results reported herein strongly implicate E3 ligase involvement and covalent cysteine reactivity in the mechanism of BRD4 degradation by CDDO-JQ1.…”

Section: Resultsmentioning

confidence: 99%

Bardoxolone conjugation enables targeted protein degradation of BRD4

Tong

Luo

Xie

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Targeted protein degradation (TPD) has emerged as a powerful tool in drug discovery for the perturbation of protein levels using heterobifunctional small molecules. E3 ligase recruiters remain central to this process yet relatively few have been identified relative to the ~ 600 predicted human E3 ligases. While, initial recruiters have utilized non-covalent chemistry for protein binding, very recently covalent engagement to novel E3’s has proven fruitful in TPD application. Herein we demonstrate efficient proteasome-mediated degradation of BRD4 by a bifunctional small molecule linking the KEAP1-Nrf2 activator bardoxolone to a BRD4 inhibitor JQ1.

show abstract

“…However, despite undeniable progress in TPD research, any degradation-based modality involves novel challenges -challenges above and beyond the already nontrivial task of developing any new drug -that must be surmounted. Recent studies [15][16][17] have reported the evolution of drug resistance after repeated exposure of cancer cells to PROTAC-based treatments. Fundamentally, this resistance seems to involve mutations not to the targeted protein itself -as might be expected for an inhibition-driven approach 18 -but rather to various components of the E3 ligase that ubiquitinates the target.…”

Section: Introductionmentioning

confidence: 99%

Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via NewIn SilicoMethodologies

Drummond¹,

Henry²,

Li³

et al. 2020

Preprint

View full text Add to dashboard Cite

Extending upon our previous publication (Drummond and Williams, J. Chem. Inf. Model.2019, 59, 1634), in this work two additional computational methods are presented to model PROTAC-mediated ternary complex structures, which are then used to predict the efficacy of any accompanying protein degradation. Method 4B, an extension to one of our previous approaches, incorporates a clustering procedure uniquely suited for considering ternary complexes. Method 4B yields the highest proportion to date of crystal-like poses in modeled ternary complex ensembles, nearing 100% in two cases and always giving a hit rate of at least 10%. Techniques to further improve this performance for particularly troublesome cases are suggested and validated. This demonstrated ability to reliably reproduce known crystallographic ternary complex structures is further established through modeling of a newly released crystal structure. Moreover, for the far more common scenario where the structure of the ternary complex intermediate is unknown, the methods detailed in this work nonetheless consistently yield results that reliably follow experimental protein degradation trends, as established through seven retrospective case studies. These various case studies cover challenging yet common modeling situations, such as when the precise orientation of the PROTAC binding moiety in one (or both) of the protein pockets has not been experimentally established. Successful results are presented for one PROTAC targeting many proteins, for different possible PROTACs targeting the same protein, and even for degradation effected by an E3 ligase that has not been structurally characterized in a ternary complex. Overall, the computational modeling approaches detailed in this work should greatly facilitate PROTAC screening and design efforts, so that the many advantages of a PROTAC-based degradation approach can be effectively utilized both rapidly and at reduced cost.

show abstract

Cellular Resistance Mechanisms to Targeted Protein Degradation Converge Toward Impairment of the Engaged Ubiquitin Transfer Pathway

Cited by 94 publications

References 39 publications

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Bardoxolone conjugation enables targeted protein degradation of BRD4

Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via NewIn SilicoMethodologies

Contact Info

Product

Resources

About