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TitleOptimization of Potent Ligands for the E3 Ligase DCAF15 and Evaluation of Their Use in Heterobifunctional Degraders.
Journal, issue, pagesJ Med Chem, Vol. 67, Issue 7, Page 5538-5566, Year 2024
Publish dateApr 11, 2024
AuthorsSimon C C Lucas / Afshan Ahmed / S Neha Ashraf / Argyrides Argyrou / Matthias R Bauer / Gian Marco De Donatis / Sylvain Demanze / Frederik Eisele / Lucia Fusani / Andreas Hock / Ganesh Kadamur / Shuyou Li / Abigail Macmillan-Jones / Iacovos N Michaelides / Christopher Phillips / Marie Rehnström / Magdalena Richter / Monica C Rodrigo-Brenni / Fiona Shilliday / Peng Wang / R Ian Storer /
PubMed AbstractUnlocking 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 ...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 , 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.
External linksJ Med Chem / PubMed:38513086
MethodsEM (single particle)
Resolution3.1 - 3.3 Å
Structure data

19406

8rox

EMDB-19406, PDB-8rox:
Structure of the human DDB1-DDA1-DCAF15 E3 ubiquitin ligase bound to compound furan 12
Method: EM (single particle) / Resolution: 3.3 Å

19407

8roy

EMDB-19407, PDB-8roy:
Structure of the human DDB1-DDA1-DCAF15 E3 ubiquitin ligase bound to compound furan 24
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

PDB-1h17:
Pyruvate Formate-Lyase (E.coli) in complex with CoA and the substrate analog oxamate

PDB-1h18:
Pyruvate Formate-Lyase (E.coli) in complex with Pyruvate

Source
  • homo sapiens (human)
KeywordsLIGASE / E3 ligase / Complex

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