Encoding BRAF inhibitor functions in protein degraders.
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Embargo End Date
ICR Authors
Authors
Miller, DSJ
Voell, SA
Sosič, I
Proj, M
Rossanese, OW
Schnakenburg, G
Gütschow, M
Collins, I
Steinebach, C
Voell, SA
Sosič, I
Proj, M
Rossanese, OW
Schnakenburg, G
Gütschow, M
Collins, I
Steinebach, C
Document Type
Journal Article
Date
2022-06-22
Date Accepted
2022-05-05
Abstract
Various BRAF kinase inhibitors were developed to treat cancers carrying the BRAFV600E mutation. First-generation BRAF inhibitors could lead to paradoxical activation of the MAPK pathway, limiting their clinical usefulness. Here, we show the development of two series of BRAFV600E-targeting PROTACs and demonstrate that the exchange of the inhibitor scaffold from vemurafenib to paradox-breaker ligands resulted in BRAFV600E degraders that did not cause paradoxical ERK activation.
Citation
RSC Medicinal Chemistry
Source Title
Publisher
ROYAL SOC CHEMISTRY
ISSN
eISSN
2632-8682
2632-8682
2632-8682
Collections
Research Team
Medicinal Chemistry 2