ELR-510444 Chemical Properties

Boiling point:

547.8±60.0 °C(Predicted)

Density 

1.37±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

insoluble in H2O; insoluble in EtOH; ≥11.9 mg/mL in DMSO

form 

solid

pka

8.28±0.10(Predicted)

color 

Light yellow to yellow

ELR-510444 Usage And Synthesis

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.

Uses

ELR510444 is a novel microtubule disruptor; inhibits MDA-MB-231 cell proliferation with IC50 of 30.9 nM; not a substrate for the P-glycoprotein drug transporter and retains activity in βIII-tubulin-overexpressing cell lines. IC50 value: 30.9 nM(MDA-MB-231 cell) [1] Target: Microtubule disruptor ELR510444 is not a substrate for the P-glycoprotein drug transporter and retains activity in βIII-tubulin-overexpressing cell lines, suggesting that it circumvents both clinically relevant mechanisms of drug resistance to this class of agents. ELR510444 also shows potent antitumor activity in the MDA-MB-231 xenograft model with at least a 2-fold therapeutic window. Studies in tumor endothelial cells show that a low concentration of ELR510444 (30 nM) rapidly alters endothelial cell shape, similar to the effect of the vascular disrupting agent combretastatin A4. ELR510444 is a novel microtubule-disrupting agent with potential antivascular effects and in vivo antitumor efficacy [1]. ELR510444 decreased HIF-1α and HIF-2α levels, reduced RCC cell viability and clonogenic survival, and induced apoptosis. VHL-deficient RCC cells were more sensitive to ELR510444-mediated apoptosis and restoration of VHL promoted drug resistance. Higher concentrations of ELR51044 promoted apoptosis independently of VHL status, possibly due to the microtubule destabilizing properties of this agent. ELR510444 significantly reduced tumor burden in the 786-O and A498 RCC xenograft models [2].

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.