2. Academic Validation
  3. Unhooking the Hook: Optimization of the Aurora A Targeting PROTAC JB170 to CCT400028, an In Vitro Degrader Chemical Probe

Unhooking the Hook: Optimization of the Aurora A Targeting PROTAC JB170 to CCT400028, an In Vitro Degrader Chemical Probe

  • J Med Chem. 2026 Jan 22;69(2):1552-1567. doi: 10.1021/acs.jmedchem.5c03024.
Jack A O'Hanlon 1 2,  Katrin Gutsche 1,  Juliane Elisabeth Müller 3,  Nihar Ranjan Prusty 1,  Amin Mirza 1,  Theodoros I Roumeliotis 4,  Hengzhang Yang 1,  Mark Stubbs 1,  Stephen T Hallett 1,  Lorenz Eing 5,  Peter Craig McAndrew 1,  Jyoti Sharma Choudhary 4,  Yann-Vaï Le Bihan 1 6,  John Caldwell 1,  Rob L M van Montfort 1 6,  Paul Workman 1 2,  Elmar Wolf 3,  Gary K Newton 1 2,  Lindsay E Evans 1 2
Affiliations

Affiliations

  • 1 Centre for Cancer Drug Discovery, The Institute of Cancer Research, London SM2 5NG, U.K.
  • 2 Cancer Research UK Children's Brain Tumour Centre of Excellence, The Institute of Cancer Research, London SM2 5NG, U.K.
  • 3 Institute of Biochemistry, University of Kiel, Rudolf-Höber-Straße 1, Kiel 24118, Germany.
  • 4 Functional Proteomics Group, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, SW3 6JB London, U.K.
  • 5 Chair of Biochemistry and Molecular Biology, University of Würzburg, Am Hubland, Würzburg 97074, Germany.
  • 6 Division of Structural Biology, The Institute of Cancer Research, London SM2 5NG, U.K.
PMID: 41524954 DOI: 10.1021/acs.jmedchem.5c03024
Abstract

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 CCT400028, 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. CCT400028 and a matched inactive control analogue fulfill the criteria for a degrader chemical probe for studying Aurora A degradation in vitro.

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