2. Academic Validation
  3. Optimization of Potent Ligands for the E3 Ligase DCAF15 and Evaluation of Their Use in Heterobifunctional Degraders

Optimization of Potent Ligands for the E3 Ligase DCAF15 and Evaluation of Their Use in Heterobifunctional Degraders

  • J Med Chem. 2024 Apr 11;67(7):5538-5566. doi: 10.1021/acs.jmedchem.3c02136.
Simon C C Lucas 1,  Afshan Ahmed 2,  S Neha Ashraf 2,  Argyrides Argyrou 2,  Matthias R Bauer 1,  Gian Marco De Donatis 2,  Sylvain Demanze 3,  Frederik Eisele 4,  Lucia Fusani 1,  Andreas Hock 2,  Ganesh Kadamur 5,  Shuyou Li 6,  Abigail Macmillan-Jones 2,  Iacovos N Michaelides 1,  Christopher Phillips 5,  Marie Rehnström 7,  Magdalena Richter 2,  Monica C Rodrigo-Brenni 8,  Fiona Shilliday 5,  Peng Wang 6,  R Ian Storer 1
Affiliations

Affiliations

  • 1 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 2 Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 3 Oncology Chemistry, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 4 Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83,Sweden.
  • 5 Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 6 Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, People's Republic of China.
  • 7 Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 8 Safety Innovation and PROTAC Safety, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
PMID: 38513086 DOI: 10.1021/acs.jmedchem.3c02136
Abstract

Unlocking novel E3 Ligases for use in heterobifunctional PROTAC degraders is of high importance to the pharmaceutical industry. Over-reliance on the current suite of ligands used to recruit E3 Ligases could limit the potential of their application. To address this, potent ligands for DCAF15 were optimized using cryo-EM supported, structure-based design to improve on micromolar starting points. A potent binder, compound 24, was identified and subsequently conjugated into PROTACs against multiple targets. Following attempts on degrading a number of proteins using DCAF15 recruiting PROTACs, only degradation of BRD4 was observed. Deconvolution of the mechanism of action showed that this degradation was not mediated by DCAF15, thereby highlighting both the challenges faced when trying to expand the toolbox of validated E3 Ligase ligands for use in PROTAC degraders and the pitfalls of using BRD4 as a model substrate.

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