Novel hybrids of (phenylsulfonyl)furoxan and anilinopyrimidine as potent and selective epidermal growth factor receptor inhibitors for intervention of non-small-cell lung cancer

J Med Chem. 2013 Jun 13;56(11):4738-48. doi: 10.1021/jm400463q. Epub 2013 May 24.

Abstract

A series of hybrids (12a-k) from (phenylsulfonyl)furoxan and anilinopyrimidine were synthesized and biologically evaluated as epidermal growth factor receptor (EGFR) inhibitors for intervention of non-small-cell lung cancer (NSCLC). Compound 12k exhibited strong and selective EGFR L858R/T790M inhibitory activity (IC50 = 0.047 μM) and displayed antiproliferative effects on EGFR mutation NSCLC cell lines HCC827 (del E746_A750) and H1975 (L858R/T790M) with IC50 values of 0.007 and 0.029 μM, respectively. Additionally, 12k released high levels of NO in H1975 cells but not in normal human cells, and its activity was diminished by pretreatment with a NO scavenger. Furthermore, 12k induced apoptosis of H1975 and HCC827 cells more strongly than WZ4002 (1), inhibited EGFR downstream signaling in H1975 cells, and suppressed the nuclear factor-κB activation in H1975 cells, while 1 had no significant effects under the same conditions. Finally, 12k substantially inhibited tumor growth in an H1975 xenograft mouse model. Overall, 12k might be a promising candidate for the treatment of NSCLC.

MeSH terms

  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Cell Line
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Enzyme Activation
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • Humans
  • Lung Neoplasms / drug therapy*
  • Male
  • Mice
  • Mice, Nude
  • NF-kappa B / metabolism
  • Neoplasm Transplantation
  • Nitric Oxide / metabolism
  • Oxadiazoles / chemical synthesis*
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Signal Transduction
  • Transplantation, Heterologous

Substances

  • 4-((6-(2-(4-(4-((4-(3-acrylamidophenoxy)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)acetoxy)hexyl)oxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide
  • Aniline Compounds
  • Antineoplastic Agents
  • NF-kappa B
  • Oxadiazoles
  • Pyrimidines
  • furoxans
  • Nitric Oxide
  • ErbB Receptors