ELR-510444

Description

ELR510444 is an inhibitor of tubulin polymerization (IC₅₀ = 10 μM) that binds to tubulin at the colchicine binding site. It induces microtubule depolymerization in A-10 cells (EC₅₀ = 21 nM). ELR510444 inhibits growth in a cancer cell line panel (IC₅₀s = 9-43 nM) via formation of multiple spindles and induction of mitotic arrest. Oral administration of ELR510444 (3-6 mg/kg) reduces tumor size in an MDA-MB-231 breast cancer mouse xenograft model in a dose-dependent manner. ELR510444 also inhibits hypoxia-inducible factor 1α (HIF-1α) in RCC4 cells in a concentration-dependent manner.

in vitro

elr510444 has potent microtubuledisrupting activity, causing a loss of intracellular microtubules and the formation of aberrant mitotic spindles and leading to mitotic arrest and apoptosis of cancer cells. elr510444 inhibited cell proliferation, inhibited the rate and extent of purified tubulin assembly potently, and displaced colchicine from tubulin, revealing that the drug directly interacts with tubulin at the colchicine-binding site [1].

in vivo

elr510444 also shows potent antitumor activity in the mda-mb-231 xenograft model with at least a 2-fold therapeutic window [1].

References

[1] risinger al, westbrook cd, encinas a, mülbaier m, schultes cm, wawro s, lewis jd, janssen b, giles fj, mooberry sl. elr510444, a novel microtubule disruptor with multiple mechanisms of action. j pharmacol exp ther. 2011 mar;336(3):652-60.