Unhooking the Hook: Optimization of the Aurora A Targeting PROTAC <b>JB170</b> to <b>CCT400028</b> , an <i>In Vitro</i> Degrader Chemical Probe
Proteolysis TArgeting Chimeras (PROTACs) can be used to target both the catalytic and noncatalytic functions of a protein, which can be particularly beneficial for proteins with important scaffolding functions like Aurora A. However, instability, poor selectivity profiles, and the hook effect often limit the applicability of PROTACs as chemical probes. In this study, we report the development of <b>CCT400028</b>, a second-generation alisertib-derived Aurora A PROTAC. The hook effect was removed through rational optimization of the CRBN-targeting warhead to decrease affinity for cereblon, which, combined with improved stability to hydrolysis, expands the range of concentrations and duration at which maximal degradation can be achieved. Potent Aurora A degradation was shown in three pediatric tumor cell lines, as well as excellent selectivity and on-target mechanism of action. <b>CCT400028</b> and a matched inactive control analogue fulfill the criteria for a degrader chemical probe for studying Aurora A degradation <i>in vitro</i>.
Authors
- Katrin Gutsche (ORCID: https://orcid.org/0000-0003-0578-1443)
- J. Choudhary
- Gary Newton (ORCID: https://orcid.org/0000-0002-2721-0089)
- Craig McAndrew (ORCID: https://orcid.org/0000-0002-1366-088X)
- Rob L. M. van Montfort (ORCID: https://orcid.org/0000-0002-5688-3450)
- Hengzhang Yang (ORCID: https://orcid.org/0000-0003-3937-4600)
- Lindsay E. Evans (ORCID: https://orcid.org/0000-0002-6950-9329)
- Amin Mirza (ORCID: https://orcid.org/0009-0002-7891-8295)
- Lorenz Eing (ORCID: https://orcid.org/0000-0002-1902-7428)
- Theodoros I. Roumeliotis (ORCID: https://orcid.org/0000-0002-3354-5643)
- Yann‐Vaï Le Bihan (ORCID: https://orcid.org/0000-0002-6850-9706)
- Jack A. O’Hanlon
- Elmar Wolf (ORCID: https://orcid.org/0000-0002-5299-6335)
- Mark Stubbs (ORCID: https://orcid.org/0000-0001-7855-9435)
- Nihar Ranjan Prusty (ORCID: https://orcid.org/0000-0003-3322-1566)
- Paul Workman
- John Caldwell
- Stephen T. Hallett
- Juliane Elisabeth Müller
Institutions
- Institute of Cancer Research (GB)
- University of Würzburg (DE)
- Discovery Centre (CA)
- Hochschule für Angewandte Wissenschaften Kiel (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Institute of Cancer Research (CA)
- Brain Tumour Research (GB)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-01-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c03024
- Citations
- 2
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 44.47