title: Isothiocyanatostilbenes as novel c-Met inhibitors.
abstract: The hepatocyte growth factor receptor (HGFR or c-Met) is a driver of multiple cancer subtypes. While there are several c-Met inhibitors in development, few have been approved for clinical use, warranting the need for continued research and development of c-Met targeting therapeutic modalities. The research presented here demonstrates a particular class of compounds known as isothiocyanatostilbenes can act as c-Met inhibitors in multiple cancer cell lines. Specifically, we found that 4,4'-Diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and 4,4'-Diisothiocyanatodihydrostilbene-2,2'-disulfonic acid (H2DIDS) had c-Met inhibitory effective doses in the low micromolar range while 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) and 4,4'-dinitrostilbene-2, 2'-disulfonic acid (DNDS) exhibited IC50s 100 to 1000 fold higher. These compounds displayed much greater selectivity for inhibiting c-Met activation compared to similar receptor tyrosine kinases. In addition, DIDS and H2DIDS reduced hepatocyte growth factor (HGF)-induced, but not epidermal growth factor (EGF)-induced, cell scattering, wound healing, and 3-dimensional (3D) proliferation of tumor cell spheroids. In-cell and cell-free assays suggested that DIDS and H2DIDS can inhibit and reverse c-Met phosphorylation, similar to SU11274. Additional data demonstrated that DIDS is tolerable in vivo. These data provide preliminary support for future studies examining DIDS, H2DIDS, and derivatives as potential c-Met therapeutics.
authors.affiliation: Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA.|Feist-Weiller Cancer Center, Shreveport, LA, USA.
authors.forename: Alana L
authors.initials: AL
authors.lastname: Gray
authors.affiliation: Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA.|Feist-Weiller Cancer Center, Shreveport, LA, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Coleman
authors.affiliation: Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA.|Feist-Weiller Cancer Center, Shreveport, LA, USA.
authors.forename: Reneau F
authors.initials: RF
authors.lastname: Castore
authors.affiliation: University of Louisiana - Monroe, Monroe, LA, USA.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Mohyeldin
authors.affiliation: University of Louisiana - Monroe, Monroe, LA, USA.
authors.forename: Khalid A
authors.initials: KA
authors.lastname: El Sayed
authors.affiliation: Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA.|Feist-Weiller Cancer Center, Shreveport, LA, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Cardelli
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D013267:Stilbenes; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; C018564:dihydro-DIDS; D017228:Hepatocyte Growth Factor; C022306:4,4'-dinitro-2,2'-stilbenedisulfonic acid; D019859:Proto-Oncogene Proteins c-met; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid
keywords: DIDS; H2DIDS; c-Met; isothiocyanatostilbenes