Presented at AACR Annual Meeting 2024
Luke Piggott, Francesco Staehli, Esteban Rodrigo Imedio
Debiopharm, Lausanne, Switzerland
Summary
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 DNA damaging agents. 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 and preliminary clinical data suggest Debio 0123 to be a good candidate for clinical development with the potential to improve therapy outcomes of patients with cancer when administered in combination with modalities that induce DNA damage, for example chemotherapies. Recently, antibody-drug-conjugates (ADCs) have shown particular promise in treating cancers through selective delivery of cytotoxic payloads to tumor cells. Sacituzumab govitecan (SG) is a TROP2 directed ADC carrying the topoisomerase 1 inhibitor (TOPO1i) payload, SN38. TROP2 expression has been observed across multiple cancer types, particularly breast, endometrial, NSCLC and CRC.