Encoding BRAF inhibitor functions in protein degraders

Various BRAF kinase inhibitors were developed to treat cancers carrying the BRAF V600E 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 BRAF V600E -targeting PROTACs...

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Bibliographic Details
Published inMedChemComm Vol. 13; no. 6; pp. 731 - 736
Main Authors Miller, Daniel S. J, Voell, Sabine A, Sosi, Izidor, Proj, Matic, Rossanese, Olivia W, Schnakenburg, Gregor, Gütschow, Michael, Collins, Ian, Steinebach, Christian
Format Journal Article
LanguageEnglish
Published CAMBRIDGE Royal Soc Chemistry 22.06.2022
Royal Society of Chemistry
RSC
Subjects
Biochemistry & Molecular Biology
Biodegradation
Chemistry
Chemistry, Medicinal
Extracellular signal-regulated kinase
Inhibitors
Kinases
Life Sciences & Biomedicine
MAP kinase
Mutation
Paradoxes
Pharmacology & Pharmacy
Science & Technology
RAF INHIBITORS
POTENT
MELANOMA
KINASE
VEMURAFENIB
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Summary:Various BRAF kinase inhibitors were developed to treat cancers carrying the BRAF V600E 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 BRAF V600E -targeting PROTACs and demonstrate that the exchange of the inhibitor scaffold from vemurafenib to paradox-breaker ligands resulted in BRAF V600E degraders that did not cause paradoxical ERK activation. Novel BRAF V600E PROTACs were developed that maintain target degradation while sparing paradoxical activation of the MAPK pathway in BRAF wt cells.
Bibliography:1
For ESI and crystallographic data in CIF or other electronic format see DOI
13
https://doi.org/10.1039/d2md00064d
C NMR and MS data; Western blots. CCDC
Electronic supplementary information (ESI) available: Supplementary Table 1, Supplementary Figures S1-S9; biological, chemical and physicochemical methods; synthetic procedures; structures
H NMR
2143596
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:2632-8682
2040-2503
2632-8682
2040-2511
DOI:10.1039/d2md00064d