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: Alana L Gray, David T Coleman, Reneau F Castore, Mohamed M Mohyeldin, Khalid A El Sayed, James A Cardelli
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 38 Pg. 41180-93 (Dec 01 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26543230 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Stilbenes
• 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid
• dihydro-DIDS
• Hepatocyte Growth Factor
• 4,4'-dinitro-2,2'-stilbenedisulfonic acid
• Proto-Oncogene Proteins c-met
• 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid

Topics

• 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid (analogs & derivatives, pharmacology)
• 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid (pharmacology)
• Animals
• Blotting, Western
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Female
• Hepatocyte Growth Factor (pharmacology)
• Humans
• Mice, Nude
• Neoplasms (drug therapy, metabolism, pathology)
• Phosphorylation (genetics)
• Proto-Oncogene Proteins c-met (metabolism)
• Stilbenes (pharmacology)
• Time Factors
• Xenograft Model Antitumor Assays