ABT-751 (E7010) has been investigated for the treatment of Lung Cancer, Non-Small Cell Lung Cancer, and Non-Small-Cell Lung Cancer.

Neuroblastoma:1.5 μM

In the HT-29 colorectal xenograft model, ABT-751 exhibited significant antitumor activity as a monotherapy and enhanced dose-dependent growth delay when combined with 5-FU. Similarly, in the Calu-6 xenograft model, ABT-751 demonstrated notable antitumor effects at 100 and 75 mg/kg/day as a single agent and displayed an enhanced dose-dependent growth delay in combination with cisplatin. In canines with lymphoma, ABT-751 presented dose-limiting toxicity, including vomiting, diarrhea, and anorexia, with a maximum tolerated dose of 350 mg/m(2) PO q24h.

ABT-751 demonstrates selective activity towards dynamic microtubules and maintains stable microtubules, explaining the persistence of acetylated and de-tyrosinated α-tubulin positive polymers at its IC90 concentration. In vitro, ABT-751 exhibits selective cytotoxicity with an IC50 of 0.6-2.6 μM in neuroblastoma cells and 0.7-4.6 μM in other solid tumor cell lines.

High-throughput screening: For HTS, USP1-UAF1 activity is monitored using ubiquitin-rhodamine 110 as a substrate, where hydrolysis of the amide bond between the C-terminal glycine of ubiquitin and rhodamine results in an increase in fluorescence. The assay is miniaturized to a 4 μL volume in a 1,536-well format and is used to screen approximately 402,701 compounds in quantitative HTS mode, with each compound tested over a range of four to five concentrations. The assay shows robust performance with an average Z'factor of 0.8 throughout the screen.

Cells, in 1640 RPMI media with FBS, are plated in triplicate onto 96 well tissue culture plates in numbers determined optimal for confluent monolayer growth (5,000 cells/well for HOS, HTB-186 Daoy; 10,000 cells/well for TC-71, RD, SK-N-AS, SK-N-DZ, LD; 30,000 cells/well for KCNR), with an automated, multichannel pipette system. Cells are incubated for 24 hours at 37 °C/5% CO2 then exposed to vehicle control (1.25% DMSO/Water), VCR (0.1–1000 nM), ABT-751 (0.1 nM–100 μM), and in 4 cell lines (SK-N-AS, KCNR, RD, TC-71) combretastatin (0.1–1000 nM) for 72 hours. Cells are fixed with trichloroacetic acid (final concentration 10%) at 4 °C, washed, then dried at room temperature, stained with SRB in 1% acetic acid and dye is then solubilized with Tris base. Optical density measurements are performed at 540 and 405 nm dual wavelengths in a Bio-Tek EL 340 UV plate reader. (Only for Reference)