A novel phosphotyrosine mimetic 4'-carboxymethyloxy-3'-phosphonophenylalanine (Cpp): exploitation in the design of nonpeptide inhibitors of pp60(Src) SH2 domain

Bioorg Med Chem Lett. 2001 Sep 3;11(17):2319-23. doi: 10.1016/s0960-894x(01)00446-2.

Abstract

The novel phosphotyrosine (pTyr) mimetic 4'-carboxymethyloxy-3'-phosphonophenylalanine (Cpp) has been designed and incorporated into a series of nonpeptide inhibitors of the SH2 domain of pp60(c-Src) (Src) tyrosine kinase. A 2.2 A X-ray crystal structure of 1a bound to a mutant form of Lck SH2 domain provides insight regarding the structure-activity relationships and supports the design concept of this new pTyr mimetic.

MeSH terms

  • Animals
  • Benzamides / chemistry*
  • Benzamides / pharmacology*
  • Binding Sites
  • Bone Resorption
  • Crystallography, X-Ray
  • Dentin / drug effects
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Molecular Mimicry
  • Mutation
  • Organophosphonates / chemistry*
  • Organophosphonates / pharmacology*
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Phosphotyrosine / chemistry*
  • Proto-Oncogene Proteins pp60(c-src) / antagonists & inhibitors*
  • Proto-Oncogene Proteins pp60(c-src) / chemistry
  • Proto-Oncogene Proteins pp60(c-src) / genetics
  • Rabbits
  • Structure-Activity Relationship
  • src Homology Domains / drug effects*

Substances

  • 4-(2-acetamido-3-(1-(3-carbamoyl-4-(cyclohexylmethoxy)phenyl)ethylamino)-3-oxopropyl)-2-(carboxymethoxy)benzenephosphonic acid
  • Benzamides
  • Enzyme Inhibitors
  • Organophosphonates
  • Phosphotyrosine
  • Proto-Oncogene Proteins pp60(c-src)

Associated data

  • PDB/1IJR