iScience (Jul 2023)
iTAG an optimized IMiD-induced degron for targeted protein degradation in human and murine cells
- 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 Montfort,
- Amine Sadok,
- Thomas F. Westbrook,
- Ian Collins,
- Rajesh Chopra
Affiliations
- Habib Bouguenina
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK; Corresponding author
- Stephanos Nicolaou
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Yann-Vaï Le Bihan
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Elizabeth A. Bowling
- Therapeutic Innovation Centre (THINC), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Cheyenne Calderon
- Therapeutic Innovation Centre (THINC), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- John J. Caldwell
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Brinley Harrington
- Therapeutic Innovation Centre (THINC), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Angela Hayes
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- P. Craig McAndrew
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Costas Mitsopoulos
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Fernando Jr. Sialana
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK; Functional Proteomics Group, The Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK
- Andrea Scarpino
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Mark Stubbs
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Arjun Thapaliya
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Siddhartha Tyagi
- Therapeutic Innovation Centre (THINC), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Hannah Z. Wang
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Francesca Wood
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Rosemary Burke
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Florence Raynaud
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Jyoti Choudhary
- Functional Proteomics Group, The Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK
- Rob L.M. van Montfort
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Amine Sadok
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Thomas F. Westbrook
- Therapeutic Innovation Centre (THINC), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Ian Collins
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Rajesh Chopra
- Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
- Journal volume & issue
-
Vol. 26,
no. 7
p. 107059
Abstract
Summary: 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.
