Simon 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
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...
March 21, 2024: Journal of Medicinal Chemistry