2. Academic Validation
  3. Encoding BRAF inhibitor functions in protein degraders

Encoding BRAF inhibitor functions in protein degraders

  • RSC Med Chem. 2022 May 5;13(6):731-736. doi: 10.1039/d2md00064d.
Daniel S J Miller 1,  Sabine A Voell 2,  Izidor Sosič 3,  Matic Proj 3,  Olivia W Rossanese 1,  Gregor Schnakenburg 4,  Michael Gütschow 2,  Ian Collins 1,  Christian Steinebach 2
Affiliations

Affiliations

  • 1 Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research London SW7 3RP UK.
  • 2 Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn D-53121 Bonn Germany c.steinebach@uni-bonn.de.
  • 3 Faculty of Pharmacy, University of Ljubljana SI-1000 Ljubljana Slovenia.
  • 4 Institute of Inorganic Chemistry, University of Bonn D-53121 Bonn Germany.
PMID: 35814929 DOI: 10.1039/d2md00064d
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.

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