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

Autor:	Lucas SCC; Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Ahmed A; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Ashraf SN; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Argyrou A; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Bauer MR; Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., De Donatis GM; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Demanze S; Oncology Chemistry, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Eisele F; Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83,Sweden., Fusani L; Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Hock A; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Kadamur G; Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Li S; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, People's Republic of China., Macmillan-Jones A; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Michaelides IN; Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Phillips C; Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Rehnström M; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden., Richter M; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Rodrigo-Brenni MC; Safety Innovation and PROTAC Safety, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Shilliday F; Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Wang P; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, People's Republic of China., Storer RI; Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Apr 11; Vol. 67 (7), pp. 5538-5566. Date of Electronic Publication: 2024 Mar 21.
DOI:	10.1021/acs.jmedchem.3c02136
Abstrakt:	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.
Databáze:	MEDLINE
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