Submitted on May 19, 2008
Revised on January 16, 2009
Accepted on January 28, 2009
Small Molecule Inhibitors of Divalent Metal Transporter-1
Peter D. Buckett1 and Marianne Wessling-Resnick1*
1 Harvard University School of Public Health
* To whom correspondence should be addressed. E-mail: wessling{at}hsph.harvard.edu.
Divalent Metal Transporter-1 (DMT1) is a divalent cation transporter that plays a key role in iron metabolism by mediating ferrous iron uptake across the small intestine. We have previously identified several small molecule inhibitors of iron uptake [Brown et al. (2004) Chem Biol 11: 407-416]. Using a cell line that stably over-expresses DMT1, we screened the ability of these inhibitors to specifically block this transporter's activity. One compound, NSC306711, inhibited DMT1 mediated iron uptake in a reversible and competitive manner. This inhibitor is a polysulphonated dye containing two copper centers. While one of these two sites could be chelated by TRIEN, copper chelation did not perturb NSC306711 inhibition of DMT1 activity. Several other polysulphonated dyes with structural features similar to NSC306711 were identified as potential DMT1 transport inhibitors. This study characterizes important pharmacological tools that can be used to probe DMT1's mechanism of iron transport and its role in iron metabolism.
