1637739-82-2Relevant articles and documents
Discovery and characterization of small molecules that target the GTPase Ral
Yan, Chao,Liu, Degang,Li, Liwei,Wempe, Michael F.,Guin, Sunny,Khanna, May,Meier, Jeremy,Hoffman, Brenton,Owens, Charles,Wysoczynski, Christina L.,Nitz, Matthew D.,Knabe, William E.,Ahmed, Mansoor,Brautigan, David L.,Paschal, Bryce M.,Schwartz, Martin A.,Jones, David N.M.,Ross, David,Meroueh, Samy O.,Theodorescu, Dan
, p. 443 - 447 (2014)
The Ras-like GTPases RalA and RalB are important drivers of tumour growth and metastasis. Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here we used protein structure analysis and virtual screening to identify drug-like molecules that bind to a site on the GDP-bound form of Ral. The compounds RBC6, RBC8 and RBC10 inhibited the binding of Ral to its effector RALBP1, as well as inhibiting Ral-mediated cell spreading of murine embryonic fibroblasts and anchorage-independent growth of human cancer cell lines. The binding of the RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasmon resonance and 1 H- 15 N transverse relaxation-optimized spectroscopy (TROSY) NMR spectroscopy. RBC8 and BQU57 show selectivity for Ral relative to the GTPases Ras and RhoA and inhibit tumour xenograft growth to a similar extent to the depletion of Ral using RNA interference. Our results show the utility of structure-based discovery for the development of therapeutics for Ral-dependent cancers.
Synthesis of novel Ral inhibitors: An in vitro and in vivo study
Yan, Chao,Theodorescu, Dan,Miller, Bettina,Kumar, Amit,Kumar, Vijay,Ross, David,Wempe, Michael F.
supporting information, p. 5815 - 5818 (2016/11/25)
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 by1H 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 IC50values 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 3.0 h post ip (50 mg/Kg) dose.