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

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.

Automated summary

To address the limitations of degron-based systems, the iTAG synthetic tag has been developed based on the mechanism of action of IMiDs/CELMoDs. It improves on both PROTAC and previous IMiDs/CeLMoDs-based tags. Through analysis, an optimal chimeric iTAG (DCD23 60aa) has been identified, which robustly degrades targets in various cell types without the "hook effect" of PROTAC-based systems. The iTAG system is a versatile tool for degrading targets across the human and murine proteome.