Poster presented at the DDR Inhibitors Summit 2023
Noemie Luong, Luke Piggott, Frederic Massiere, Anne Bellon, Esteban Rodrigo Imedio
Debiopharm International SA, Lausanne, Switzerland
The WEE1 tyrosine kinase is activated upon DNA damage and is a key regulator of cell cycle progression. It 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, in conjunction with additional genetic alterations and/or in addition to DNA damaging agents, results in mitotic catastrophe and apoptosis of cancer cells, and is an attractive approach for treating cancer.
Debio 0123 is an investigational, orally-available, selective ATP-competitive WEE1 inhibitor. Its main characteristics are an IC50 on WEE1 in the low nanomolar range, high selectivity, in particular lacking PLK1 and PLK2 inhibition, and good efficacy in animal models in several tumor types, as monotherapy or in combination with DNA damaging agents, such as etoposide and carboplatin.
Debio 0123 is currently being tested in two clinical studies, as monotherapy and in combination with carboplatin, in patients with advanced solid tumors. At the highest doses tested so far, a consistent pharmacodynamic effect on the downstream marker pCDC2 has been observed, suggesting target engagement.