iTAG an optimized IMiD-induced degron for targeted protein degradation in human and murine cells

• DOI: 10.1016/j.isci.2023.107059
• Publication Date: 2023-06-07T18:18:30Z
• Authors: Habib Bouguenina; Stephanos Nicolaou; Yann-Vaï Le Bihan; Elizabeth A. Bowling; Cheyenne Calderon; John J. Caldwell; Brinley Harrington; Angela Hayes; P. Craig McAndrew; Costas Mitsopoulos; Fernando Jr. Sialana; Andrea Scarpino; Mark Stubbs; Arjun Thapaliya; Siddhartha Tyagi; Hannah Z. Wang; Francesca Wood; Rosemary Burke; Florence Raynaud; Jyoti Choudhary; Rob L.M. van Mont...; Amine Sadok; Thomas F. Westbrook; Ian Collins; Rajesh Chopra
• Keywords: Degron; Degradation

To address the limitation associated with degron based systems, we have developed iTAG, a synthetic tag on IMiDs/CELMoDs mechanism of action that improves and addresses limitations both PROTAC previous IMiDs/CeLMoDs tags. Using structural sequence analysis, systematically explored native chimeric containing domains (DCDs) evaluated their ability to induce degradation. We identified optimal iTAG(DCD23 60aa) elicits robust degradation targets across cell types subcellular localizations without exhibiting well documented "hook effect" PROTAC-based systems. showed iTAG can also target by murine CRBN enabled exploration natural neo-substrates be degraded CRBN. Hence, system constitutes versatile tool degrade human proteome.