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Vinylpyridine as a Tunable Covalent Warhead Targeting C797 in EGFR.

Nils PembertonNina CompagneArgyrides ArgyrouEmma EvertssonAnders GunnarssonJason G KettleJonathan P OrmeRichard A Ward
Published in: ACS medicinal chemistry letters (2024)
To further facilitate the discovery of cysteine reactive covalent inhibitors, there is a need to develop new reactive groups beyond the traditional acrylamide-type warheads. Herein we describe the design and synthesis of covalent EGFR inhibitors that use vinylpyridine as the reactive group. Structure-based design identified the quinazoline-containing vinylpyridine 6 as a starting point. Further modifications focused on reducing reactivity resulted in substituted vinyl compound 12 , which shows high EGFR potency and good kinase selectivity, as well as significantly reduced reactivity compared to the starting compound 6 , confirming that vinylpyridines can be applied as an alternative cysteine reactive warhead with tunable reactivity.
Keyphrases
  • small cell lung cancer
  • tyrosine kinase
  • epidermal growth factor receptor
  • small molecule
  • fluorescent probe
  • living cells
  • molecular docking
  • cancer therapy
  • energy transfer
  • drug delivery
  • protein kinase