Sulfonylbenzoyl-nitrostyrenes: Potential Bisubstrate Type Inhibitors of the EGF-receptor Tyrosine Protein Kinase

J Med Chem. 1991 Aug;34(8):2328-37. doi: 10.1021/jm00112a003.

Abstract

The synthesis and biological activities of a series of sulfonylbenzoyl-nitrostyrene derivatives, a novel class of selective bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase, are described. The most potent derivatives inhibited the EGF-R tyrosine kinase, using angiotensin II as exogenous substrate, with IC50 values of less than or equal to 1 microM. No inhibition of the v-abl tyrosine kinase or the serine/threonine kinases PKC and PK-A was observed. In addition, active derivatives (compounds 5 and 12) effectively blocked the autophosphorylation of the EGF-R in vitro. Starting from the acids 5, 7, and 9, a series of esters, amides, and peptides was synthesized with the aim of increasing cellular penetration. Amides 14-18 showed potent antiproliferative effects using the EGF-dependent Balb/MK mouse epidermal keratinocyte cell line. Additionally, with the amide 14 inhibition of EGF-R autophosphorylation was demonstrated in the A431 cell line. CAMM studies using a computer-generated model for the transition state of the gamma-phosphoryl transfer from ATP to a tyrosine moiety and fitting experiments using the highly potent derivative 7 (IC50 value = 54 nM) support the hypothesis that the sulfonylbenzoyl group mimics a diphosphate moiety in the transition state. These results demonstrate that the rational design of tyrosine kinase inhibitors, using the inhibitory nitrostyrene moiety as a tyrosine mimic together with the sulfonylbenzoyl moiety as a diphosphate mimic, leads to highly potent and selective multisubstrate type inhibitors.

MeSH terms

  • Angiotensin II / metabolism
  • Animals
  • Benzoates / chemistry
  • Benzoates / pharmacology*
  • Cell Division / drug effects
  • Cell Line
  • Chemical Phenomena
  • Chemistry
  • Computer Simulation
  • Crystallography
  • Enzyme Activation / drug effects
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Nitro Compounds / chemistry
  • Nitro Compounds / pharmacology
  • Phosphorylation
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Styrenes / chemistry
  • Styrenes / pharmacology*
  • Sulfones / chemistry
  • Sulfones / pharmacology*

Substances

  • Benzoates
  • Nitro Compounds
  • Styrenes
  • Sulfones
  • Angiotensin II
  • Epidermal Growth Factor
  • ErbB Receptors
  • Protein-Tyrosine Kinases