Synthesis of novel Ral inhibitors: An in vitro and in vivo study

Bioorg Med Chem Lett. 2016 Dec 1;26(23):5815-5818. doi: 10.1016/j.bmcl.2016.10.021. Epub 2016 Oct 12.

Abstract

Chemical synthesis was performed to produce a series of 6-amino-1,3-disubstituted-4-phenyl-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile compounds (14-57) which were characterized by 1H NMR, 13C NMR and LC/MS-MS. These compounds were assessed for their effect on the in vitro anchorage independent growth of human lung cancer cell line H2122 and IC50 values calculated. Two of the more potent compounds, BQU057 40 and BQU082 57 also displayed a dose dependent effect on RalA and RalB activity in H2122 spheroids using the common RalBP1 pull-down assay. Mouse PK and tissue distribution studies on 40 and 57 were performed and demonstrated that parent drug was present in tumor 3.0h post ip (50mg/Kg) dose.

Keywords: Chemical synthesis; Ral inhibitor; Tissue distribution.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Discovery
  • Humans
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Nitriles / chemistry
  • Nitriles / pharmacology
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology*
  • Tissue Distribution
  • ral GTP-Binding Proteins / antagonists & inhibitors*
  • ral GTP-Binding Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Nitriles
  • Pyrazoles
  • Ralb protein, human
  • RALA protein, human
  • ral GTP-Binding Proteins