Abstract 4423: Antitumor activity of the novel oral highly selective Wee1 inhibitor Debio 0123
Authors: O'Dowd Colin , Gavory Gerald , Burkamp Frank , Treder Adam , Boyd Caroline , Harrison Tim , Massière Frederic , Glück Astrid , Chardonnens Christophe , Zaffalon Andrea , Rigotti Stefania , Mader Robert , Vuagniaux Grégoire , Chessex Anne Vaslin 
Published: August 2019

Abstract
Background: The Wee1 tyrosine kinase is activated upon DNA damage and regulates the G2-M cell cycle checkpoint. Inhibition of Wee1, in conjunction with additional genetic alterations and/or addition of a DNA damaging agent, results in mitotic catastrophe and apoptosis of cancer cells, offering an attractive approach to treating cancer. The aim of the present study was to characterize the pharmacological properties of the newly discovered, orally available, and highly selective Wee1 inhibitor Debio 0123.
Methods: Profiling of Debio 0123 was performed on 465 selected kinases in a cell-free system. Effects of Debio 0123 on downstream signaling were analyzed by ELISA and western blot in HT29 (colorectal adenocarcinoma) and A427 (lung carcinoma) cell lines. The in vitro growth inhibition activity of Debio 0123 was defined in a broad number of human cancer cell lines after 72h using a proliferation monolayer assay. Debio 0123 in vivo anti-tumoral activity was assessed in an A427 subcutaneous xenograft model in athymic nude mice. Debio 0123 pharmacodynamic effects were also evaluated after oral dosing in surrogate tissues of mice, rats and monkeys by immunohistochemistry.
Results: Debio 0123 is a highly selective ATP-competitive Wee1 inhibitor with an IC50 in the low nanomolar range. Debio 0123 inhibited Cdk1 (Cdc2) phosphorylation at Y15, a direct substrate of Wee1 in cells. Debio 0123 also induced dose- and time-dependent increased mitosis and unrepaired DNA damage shown by increased phosphorylation of histone H3 and γH2AX foci formation. In vitro activity was further studied in a large panel of cancer cell lines. Debio 0123 demonstrated submicromolar cytotoxic activity on multiple cell lines from various histotypes. In vivo, Debio 0123 was shown to inhibit phosphorylation of Cdk1 in tissues of multiple species and induction of DNA damage in a xenograft model. When administered orally once daily for 28 consecutive days, Debio 0123 induced dose-dependent anti-tumor activity and was well tolerated at all doses tested. At 30 mg/kg, treatment with Debio 0123 resulted in tumor regression.
Conclusion: Altogether these results demonstrate that Debio 0123 is a highly selective and potent Wee1 inhibitor able to prevent Cdk1 phosphorylation in multiple species and to induce apoptosis through accumulation of unrepaired DNA damage both in vitro and in vivo that result in tumor regression. The advancement of Debio 0123 into clinical studies may provide improved therapeutic outcomes for patients with cancer.
Citation Format: Colin O'Dowd, Gerald Gavory, Frank Burkamp, Adam Treder, Caroline Boyd, Tim Harrison, Frederic Massière, Astrid Glück, Christophe Chardonnens, Andrea Zaffalon, Stefania Rigotti, Robert Mader, Grégoire Vuagniaux, Anne Vaslin Chessex. Antitumor activity of the novel oral highly selective Wee1 inhibitor Debio 0123 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4423.