Presented at AACR Annual Meeting 2022
Luke Piggott, Anne Vaslin-Chessex, Noémie Luong, Benjamin Tschumi, Grégoire Vuagniaux
Debiopharm International SA, Lausanne, Switzerland
Introduction
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. Small cell lung cancer (SCLC) is an aggressive disease with poor clinical outcomes that carries a high mutational burden and genomic instability. Here we investigated the ability of Debio 0123 to enhance SCLC response to standard of care (SOC) DNA damaging agents carboplatin and etoposide in vitro and in vivo.