ENMD-1198, an Orally Active Tubulin-Binding Agent, Reduces HIF-1α and STAT3 Activity

Hepatocellular carcinoma (HCC) is the fifth most cancer worldwide, with a continuously increasing incidence. HCC represents a hyper vascularized tumor and its progression is closely related to angiogenesis. Hepatocellular carcinoma overexpresses the vascular endothelial growth factor (VEGF). The transcription factor HIF-1α also plays a central role in HCC progression and angiogenesis. Furthermore, the transcription factor signal transducer and activator of transcription 3 (STAT3), yet another inducer of angiogenesis in terms of up-regulating VEGF, is constitutively activated in HCC. 2ME2 impairs activation of HIF-1α through destabilization of microtubules, in addition to exhibiting antiproliferative and pro-apoptotic effects. In this study, ENMD-1198, a new analog of 2-methoxyestradiol, displays both antiangiogenic and vascular-disrupting properties. It is an orally active, microtubule disrupting agent that leads to the arrest of cell division and apoptosis in tumor cells. ENMD-1198 also reduces HIF-1alpha and STAT3 activity in human HCC cells. It also inhibits growth and vascularization.

ENMD 1198 an Orally Active Tubulin Binding Agent Reduces HIF 1α and STAT3 Activity 2021 03 06 - ENMD-1198, an Orally Active Tubulin-Binding Agent, Reduces HIF-1α and STAT3 Activity

ENMD-1198 dose-dependently elicits significant antiproliferative effects on HCC cells with an IC50 at 2.5 μM in HUH-7 and HepG2 cells. It substantially disrupts EGF signaling in terms of diminishing downstream phosphorylation of the substrates p44/42 MAPK and Akt. Moreover, ENMD-1198 markedly reduces the activation of STAT3, an important transcription factor for regulating VEGF-A in cancer cells. In addition, it significantly inhibits both EGF- and HGF-mediated cancer cell migration and invasiveness. It also effectively inhibits the growth of hepatocellular carcinoma through direct effects on the tumor cells, and also through inhibition of angiogenesis. ENMD-1198 -based combination treatments reduce tumor burden but do not eradicate the tumor in mice. ENMD-1198 treatment protects the bone against tumor-induced osteolysis in vivo.

In summary, ENMD-1198 is an analog of 2ME2 with antiproliferative and antiangiogenic activity. Moreover, it effectively diminishes both HIF-1α and STAT3 activation in HCC cells, which represent important mediators of HCC progression.


Moser C, et al. BMC Cancer. 2008 Jul 23;8:206.