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
  • 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 [email protected].
  • 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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