Isothiocyanatostilbenes as novel c-Met inhibitors
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Alana L. Gray1,2, David T. Coleman1,2, Reneau F. Castore1,2, Mohamed M. Mohyeldin3, Khalid A. El Sayed3, James A. Cardelli1,2
1Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA
2Feist-Weiller Cancer Center, Shreveport, LA, USA
3University of Louisiana - Monroe, Monroe, LA, USA
James A. Cardelli, e-mail: firstname.lastname@example.org
Keywords: c-Met, isothiocyanatostilbenes, DIDS, H2DIDS
Received: August 05, 2015 Accepted: September 17, 2015 Published: October 31, 2015
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.
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