2. Academic Validation
  3. Synthesis of novel Ral inhibitors: An in vitro and in vivo study

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.
Chao Yan 1,  Dan Theodorescu 2,  Bettina Miller 3,  Amit Kumar 3,  Vijay Kumar 3,  David Ross 3,  Michael F Wempe 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Colorado, Aurora, CO 80045, USA; Department of Surgery, University of Colorado, Aurora, CO 80045, USA.
  • 2 Department of Pharmacology, University of Colorado, Aurora, CO 80045, USA; Department of Surgery, University of Colorado, Aurora, CO 80045, USA; University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA.
  • 3 Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO 80045, USA.
  • 4 Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO 80045, USA. Electronic address: michael.wempe@ucdenver.edu.
PMID: 27825764 DOI: 10.1016/j.bmcl.2016.10.021
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.

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