Presented at AACR Annual Meeting 2025
Luke Piggott1, Diana Gomes1, Paula Martinez2,Violeta Serra2
1Debiopharm International, Lausanne, Switzerland
2Vall D’Hebron Institute of Oncology, Barcelona, Spain
Summary
Debio 0123 is an investigational, orally bioavailable, highly selective and brain penetrant adenosine triphosphate (ATP)-competitive inhibitor of the WEE1 tyrosine kinase currently in phase 1 clinical trials. 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]) through phosphorylation of Tyr15. WEE1 is an attractive opportunity as a therapeutic target in cancer therapy, either in cells relying on cell cycle checkpoints regulated by WEE1 or to potentiate DNA damaging agents. The proposed mechanism of action of Debio 0123 involves promoting uncontrolled entry into mitosis with accumulated DNA damage and, ultimately, cell death via mitotic catastrophe.
The nonclinical data suggested Debio 0123 has the potential to improve therapy outcomes of patients with cancer and is currently in clinical development as monotherapy or in combinations.
PKMYT1 is also a negative regulator of CDK1 through phosphorylation at Thr14. Thus, Debio 0123 in combination with the PKMYT1 inhibitor lunresertib induces strong phosphorylation of CDK1 at both Tyr15 and Thr14 potentially leading to premature mitotic entry, chromosome pulverization and cancer cell death.