Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs

Eur J Med Chem. 2018 May 25:152:76-86. doi: 10.1016/j.ejmech.2018.04.019. Epub 2018 Apr 11.

Abstract

Rather than by directly focusing on the ever-changing ALK mutants, here we report an alternative strategy to overcome the drug resistance caused by treatment of ALK inhibitors by developing ALK and Hsp90 dual targeting inhibitors. Since Hsp90 is a molecular chaperone that regulates the maturation, activation and stability of numerous "client proteins" including ALK, dual targeting ALK and Hsp90 may bring more benefits and efficacy against drug resistance of ALK inhibitors. By using our previously developed ALK inhibitor 6 and the clinical Hsp90 inhibitors AUY922 or AT13387 as the templates, we developed several series of resorcinol tethered 2,4-diaminopyrimidines as ALK/Hsp90 dual inhibitors bearing various linkers at different linking sites. Compound 10h and 10j showed high potency against ALK (17.3 vs 9.8 nM) and Hsp90α (100 vs 40 nM). They also have high potency against ALK resistant mutants, especially the gatekeeper mutation ALKL1196M. Both compounds showed strong antiproliferative activity against the ALK-addictive H3122 cells (11 vs 13 nM). The dual functioning mechanism is further confirmed by their down-regulation of the Hsp90 clients ALK and AKT, and up-regulation of the chaperone protein Hsp70 in H3122 cells.

Keywords: Antiproliferative activity; Drug resistance; Dual inhibitor; Heat shock protein 90 (Hsp90); Tyrosine kinase ALK.

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Resorcinols / chemistry
  • Resorcinols / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Resorcinols
  • 2,4-diaminopyrimidine
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • resorcinol