VERU-111 is an Orally Active Tubulin Inhibitor
Posted On 2019-08-10
Microtubules play a critical role in the proliferation of cancer cells. Meanwhile, microtubule dynamics is therefore one of the most productive therapeutic targets for cancer treatment. Microtubule-targeting agents can interfere with functions of microtubules, thereby disrupting the formation of the mitotic spindle, eventually leading to mitotic arrest at the metaphase/anaphase transition. The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic modalities. Tubulins play a major role in cell dynamics, thus are important molecular targets for cancer therapy. However, VERU-111 is a potent and orally bioavailable α and β tubulin inhibitor with antiproliferative activity.
VERU-111 is a potent and orally bioavailable α and β tubulin inhibitor with antiproliferative activity.
In vitro, VERU-111 displays strong antiproliferative activity. It inhibits human melanoma cell lines A375, WM164, and M14 growth, and the IC50s range from 5.6 to 8.1 nM. Furthermore, VERU-111 inhibits the growth of PanCa cells in a dose and time-dependent manner. The IC50 of VERU-111 is 25, 35 and 35 nM in Panc-1, AsPC-1 and HPAF-II, respectively after 24 h treatment, while 48 h post-treatment it was 11.8, 15.5, and 25 nM. VERU-111 significantly inhibited the mRNA expression of βIII and βIV-tubulins in PanCa cells. VERU-111 inhibits βIII-tubulin and causes disruption of microtubular dynamics in PanCa cells. It inhibits migration and invasive potential of PanCa cells.
Moreover, VERU-111 arrested Panc-1 and AsPC-1 cells in G2/M phase in a dose-dependent manner. It effectively inhibits the expression of cyclin B1, cdc2 and cdc25c in PanCa (Panc-1 and AsPC-1) cells. Meanwhile, it enhances the phosphorylation of cdc2. VERU-111 treatment results in apoptosis induction in both Panc-1 and AsPC-1 cells.
In vivo, VERU-111 effectively inhibits tumor growth as compared to vehicle-treated group. None of the mouse show any apparent toxicity as we observed constant increase of body weight in VERU-111 treated mice.
All in all, VERU-111 has excellent potential as monotherapy or in combination with conventional therapeutic regimens for PanCa treatment.
Kashyap VK, et al. J Exp Clin Cancer Res. 2019 Jan 23;38(1):29.