Abstract B190: Antitumor effects of ABC131, a novel diaminothiazole inhibitor of tubulin

• Published in: Molecular cancer therapeutics 2018-01, Vol.17 (1_Supplement), p.B190-B190
• Main Authors: Smith, Charles D., Schrecengost, Randy S., Zhuang, Yan, Maines, Lynn W., Keller, Staci N., Smith, Ryan A., Green, Cecelia L.
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-17-B190

Background: Several established chemotherapy drugs, including vinca alkaloids and paclitaxel, block tumor cell division by disrupting microtubule dynamics, ultimately leading to apoptosis. For decades, these drugs have remained central components for cancer therapy despite their limitations, which include hematologic and neurologic toxicities and the propensity for tumor cells to develop resistance to these agents. In characterizing a new series of diaminothiazoles, we focused on defining the mechanism of action and the antitumor activity of a novel compound (ABC131). Materials and Methods: A library of DATs was synthesized by reaction of substituted phenylisothiocyanates, tetramethylguanidine and substituted phenylacylbromides, and tested for cytotoxicity against several tumor cell lines. These compounds were further assessed for their mechanism(s) of action using a variety of cellular and biochemical assays, and selected compounds were tested in vivo for toxicity and antitumor activity in syngeneic allograft models using PAN02 (pancreatic), B16 (melanoma) or TRAMP (prostate) tumor cells. Results: A library of more than 90 diaminothiazoles was produced, and these compounds demonstrated IC50s for cytotoxicity against PAN02 cells ranging from 0.04 to >100 μM. Several of these compounds depolymerized microtubules in cells. One such compound, ABC131, was selected for detailed characterization because of the potent antiproliferative activity against a panel of murine and human tumor cells (IC50s ~30-300 nM). ABC131 caused dose-dependent microtubule depolymerization in cells, in parallel with G2/M cell cycle arrest and apoptosis. Kinome profiling demonstrated that ABC131 did not significantly inhibit any of more than 400 protein kinases, including cyclin-dependent kinases, which are inhibited by several compounds within this library. Importantly, transport studies demonstrated that ABC131 is not a substrate for P-glycoprotein, a well-established mechanism for resistance to many other anti-microtubule drugs. Oral administration of ABC131 at doses as low as 2 mg/kg/day inhibited tumor growth in all models tested (PAN02, B16, and TRAMP). Pharmacokinetic and biodistribution analyses of ABC131 demonstrated >10-fold IC50 levels in the plasma and tumors following oral dosing of mice. Although ABC131 was rapidly cleared from the plasma, liver, and brain, >IC50 levels of ABC131 persisted in tumors for at least 7 hours after oral dosing. No hematologic or major organ tox