Dp44mT | Metal chelator

Dp44mT (152095-12-0) is a metal chelator with potent antitumor activity.^1,2 It displayed an average IC₅₀ of 30 nM over 28 cancer cell lines (IC₅₀ range was 5 nM to 400 nM).² Dp44mT retained its antiproliferative activity in both etoposide-resistant MCF-7/VP clones (MCF-7 breast cancer cells) and vinblastine-resistant KB-VB1 clones (KB3-1 epidermoid carcinoma cells) with an IC₅₀ = 12 nM for both lines.² The potency of Dp44mT has been attributed to the high redox activity of the Dp44mT-Fe complex leading to cytotoxic ROS generation. The antitumor activity of Dp44mT may also be mediated by a redox active copper complex that causes cellular glutathione depletion and lysosomal damage.^3,4 It also inhibited T-cell activation and prevented CD25 up-regulation via a copper-dependent mechanism.⁵ Dp44mT has recently been shown to effectively inhibit c-Met though metalloprotease-mediated cleavage and lysosomal degradation.⁶

References/Citations:

1) Yuan et al. (2004), Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment; Blood, 104 1450
2) Whitnall et al. (2006), A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics., Proc. Natl. Acad. Sci. USA 103 14910
3) Lovejoy et al. (2011), Antitumor activity of metal-chelating compound Dp44mT is mediated by formation of a redox-active copper complex that accumulates in lysosomes; Cancer Res., 71 5871
4) Gutierrez et al. (2014), The anticancer agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbzone (Dp44mT) overcomes prosurvival autophagy by two mechanisms: persistent reduction of autophagosome synthesis and impairment of lysosomal integrity; J. Biol. Chem., 289 33568
5) Gundelach et al. (2013), The anticancer drug Dp344mT inhibits T-cell activation and CD25 through a copper-dependent mechanism; FASEB J., 27 782
6)Park et al. (2020), Thiosemicarbazones suppress expression of the c-Met oncogene by mechanisms involving lysosomal degradation and intracellular shedding; J. Biol.Chem., 295 481