iTAG an optimized IMiD-induced degron for targeted protein degradation in human and murine cells.
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Authors
Bouguenina, H
Nicolaou, S
Le Bihan, Y-V
Bowling, EA
Calderon, C
Caldwell, JJ
Harrington, B
Hayes, A
McAndrew, PC
Mitsopoulos, C
Sialana, FJ
Scarpino, A
Stubbs, M
Thapaliya, A
Tyagi, S
Wang, HZ
Wood, F
Burke, R
Raynaud, F
Choudhary, J
van Montfort, RLM
Sadok, A
Westbrook, TF
Collins, I
Chopra, R
Nicolaou, S
Le Bihan, Y-V
Bowling, EA
Calderon, C
Caldwell, JJ
Harrington, B
Hayes, A
McAndrew, PC
Mitsopoulos, C
Sialana, FJ
Scarpino, A
Stubbs, M
Thapaliya, A
Tyagi, S
Wang, HZ
Wood, F
Burke, R
Raynaud, F
Choudhary, J
van Montfort, RLM
Sadok, A
Westbrook, TF
Collins, I
Chopra, R
Document Type
Journal Article
Date
2023-07-21
Date Accepted
2023-06-01
Abstract
To address the limitation associated with degron based systems, we have developed iTAG, a synthetic tag based on IMiDs/CELMoDs mechanism of action that improves and addresses the limitations of both PROTAC and previous IMiDs/CeLMoDs based tags. Using structural and sequence analysis, we systematically explored native and chimeric degron containing domains (DCDs) and evaluated their ability to induce degradation. We identified the optimal chimeric iTAG(DCD23 60aa) that elicits robust degradation of targets across cell types and subcellular localizations without exhibiting the well documented "hook effect" of PROTAC-based systems. We showed that iTAG can also induce target degradation by murine CRBN and enabled the exploration of natural neo-substrates that can be degraded by murine CRBN. Hence, the iTAG system constitutes a versatile tool to degrade targets across the human and murine proteome.
Citation
iScience, 2023, 26 (7), pp. 107059 -
Source Title
iScience
Publisher
CELL PRESS
ISSN
2589-0042
eISSN
2589-0042
2589-0042
2589-0042
Collections
Research Team
Medicinal Chemistry 4
Prote & Metabolomics Fac
Hit Discov Struct Design
Clinical Pharma & Trials
Prote & Metabolomics Fac
Hit Discov Struct Design
Clinical Pharma & Trials