Presented at AACR Annual Meeting 2023
Luke Piggott, Noémie Luong, Christophe Chardonnens, Frederic Massierre, Annett Kunze, Anne Vaslin-Chessex
Debiopharm International SA, Lausanne, Switzerland
Debio 0123 is an investigational, orally bioavailable, highly selective, adenosine triphosphate (ATP)-competitive inhibitor of the WEE1 tyrosine kinase. WEE1 is a key regulator of cell cycle progression that influences entry into mitosis by modulating activity of cyclin-dependent kinase 1 (CDK1, also referred to as cell division cycle 2 [CDC2]). Inhibition of WEE1 presents an opportunity as a therapeutic target in cancer therapy, either in cells relying on cell cycle checkpoints regulated by WEE1 or to potentiate chemotherapy and radiation therapy1. The proposed mechanism of action of Debio 0123 involves promoting entry into uncontrolled mitosis for cells with accumulated DNA damage and, ultimately, cell death via mitotic catastrophe.
The nonclinical data suggest Debio 0123 to be a good candidate for clinical development with the potential to improve therapy outcomes of patients with cancer, as monotherapy or when administered in combination with modalities that induce DNA damage, for example chemotherapies and radiotherapy. Glioblastoma (GBM) is one of the most aggressive and hard-totreat cancers with a 5-year survival rate of 6.8%, in part due to the presence of the blood brain barrier (BBB) that prevents most therapeutics from reaching the tumors at efficacious concentrations. Here we investigated the ability of Debio 0123 to cross the BBB and enhance response to standard of care (SOC) DNA damaging agent temozolomide (TMZ) in vitro and in vivo.
(1) Do K. et al., Cell Cycle. 2013 Oct 1;12(19):3159-64
(2) O’Dowd et al., Antitumor activity of the novel oral highly selective WEE1 inhibitor Debio 0123, AACR 2019 abstract #4423
(3) Workman et al., British Journal of cancer. (2010) 102, 1555-1577
(4) Huang et al., J. Med. Chem. 2021, 64, 17, 13004