A Buchwald-Hartwig Protocol to Enable Rapid Linker Exploration of Cereblon E3-Ligase PROTACs*.

Thomas G Hayhow, Rachel E A Borrows, Coura R Diène, Gary Fairley, Charlene Fallan, Shaun M Fillery, James S Scott, David W Watson

Journal: Chemistry (Weinheim an der Bergstrasse, Germany) 2021;26(70):16818-16823

PMID: 32706492

Full Text on Wiley View on PubMed

Abstract

A palladium-catalysed Buchwald-Hartwig amination for lenalidomide-derived aryl bromides was optimised using high throughput experimentation (HTE). The substrate scope of the optimised conditions was evaluated for a range of alkyl- and aryl- amines and functionalised aryl bromides. The methodology allows access to new cereblon-based bifunctional proteolysis targeting chimeras with a reduced step count and improved yields.

Address: Medicinal Chemistry, Oncology R&D, Research and Early Development, AstraZeneca, Cambridge Science Park, Unit 310 Darwin Building, Cambridge, CB4 0WG, UK.; Medicinal Chemistry, Oncology R&D, Research and Early Development, AstraZeneca, Macclesfield Campus, Etherow Building, Silk Road Industrial Estate, Macclesfield, SK10 2NA, UK.

DOI: 10.1002/chem.202003137

Link outs

Free resources

Other Literature Sources:

https://www.lens.org/lens/search/patent/list?q=ref...

Subscription / membership required

Full Text Sources:

https://doi.org/10.1002/chem.202003137

MeSH Terms: Amination, Amines, Bromides, Lenalidomide, Ligands, Proteolysis, Ubiquitin-Protein Ligases