Antitumor Effects Of Abc131, A Novel Diaminothiazole Inhibitor Of Tubulin

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 IC 50 s for cytotoxicity against PAN02 cells ranging from 0.04 to u003e100 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 (IC 50 s ~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 u003e10-fold IC 50 levels in the plasma and tumors following oral dosing of mice. Although ABC131 was rapidly cleared from the plasma, liver, and brain, u003eIC 50 levels of ABC131 persisted in tumors for at least 7 hours after oral dosing. No hematologic or major organ toxicity was observed in mice treated with ABC131 at 500 mg/kg/day for 7 days. A model of peripheral neuropathy in rats demonstrated markedly reduced toxicity for ABC131 compared with paclitaxel. Conclusions: ABC131 is a new potential anticancer agent with several advantages over established anti-microtubule drugs, including oral bioavailability, lack of sensitivity to P-glycoprotein, lack of hematologic toxicity, and reduced neuropathy. These properties of ABC131 are highly supportive of its development as an anticancer drug. Citation Format: Charles D. Smith, Randy S. Schrecengost, Yan Zhuang, Lynn W. Maines, Staci N. Keller, Ryan A. Smith, Cecelia L. Green. Antitumor effects of ABC131, a novel diaminothiazole inhibitor of tubulin [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B190.