A Modular Chemistry Platform for the Development of a Cereblon E3 Ligase‐Based Partial PROTAC Library
Year: 2023
Type: article
Abstract: Proteolysis targeting chimeras (PROTACs) are a promising therapeutic strategy to selectively promote the degradation of protein targets by exploiting the ubiquitin-proteasome system. Among the limited number of E3 ligase ligands discovered for the PROTAC technology, ligands of cereblon (CRBN) E3 ligase, such as pomalidomide, thalidomide, or lenalidomide, are the most frequently used for the development of PROTACs. Our group previously reported that a phenyl group could be tolerated on the C4-position of lenalidomide as the ligand of CRBN to develop PROTACs. Herein, we report a modular chemistry platform for the efficient attachment of various ortho-, meta-, and para-substituted phenyls to the C4-position of the lenalidomide via Suzuki cross-coupling reaction, which allows the systematic investigation of the linker effect for the development of PROTACs against any target. We examined the substrate scope by preparing twelve lenalidomide-derived CRBN E3 ligase ligands with different linkers.
Source: ChemBioChem
Institution: University of Wisconsin–Madison
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,020
Funders: Wisconsin Alumni Research Foundation, University of Wisconsin-Madison, University of Wisconsin Carbone Cancer Center, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Division of Graduate Education
Awards: G1712026730, G245808252, G2560624041, G4004214011, G42679306, Development of Broad-Spectrum Antiviral Therapeutics by Destabilizing the Main Protease of Coronaviruses, G5813506420, G5954588232, G6238290905, G7847486505, G843635962, G8794924737, G8821677074, G9000023674, G9000265189, G9000352744
OpenAlex ID: W4383559433