Debio 0123 is a Wee1 kinase inhibitor currently in phase I research in refractory solid tumors. The compound is being developed based on the deepened understanding of the DNA damage response (DDR) of cancer cells. Inhibition of WEE1 prevents cells to arrest or repair DNA damages and force them to prematurely continue through the cell cycle, therefore accumulating unrepaired DNA damages ultimately leading to cell death. The compound is being developed in light of the need to improve cancer patients’ treatment response and to overcome treatment resistance to current therapies. Pre-clinical models have shown anti-tumor activity both as a single agent and in combination with carboplatin. The advancement of Debio 0123 into clinical studies will assess the therapeutic results for cancer patients in various tumor types.
Inhibition of Wee1 Kinase
Forced arrest of DDR leading to apoptosis
Being researched in:
- Solid tumors
Initially discovered by Almac Discovery before being licensed by Debiopharm, Debio 0123 could prevent tumor growth by inhibiting Wee1 thereby disrupting DDR through the G2/M and S phase checkpoints
Ongoing Phase 1 clinical studies are investigating Debio 0123 as monotherapy in solid tumors and in combination with SoC in selected tumor types including small cell lung cancer and glioblastoma
Focus on Debio 0123 Mode of Action
Wee1 is a key regulator of the G2/M and S phase checkpoints, activated in response to DNA damage, that allow cells to repair their DNA before resuming the cell cycle. Inhibition of Wee1, particularly in combination with DNA damaging agents, induces an overload of arrests in the DNA damage response process. Also, in conjunction with the failure of other checkpoints, such as G1 controlled by p53, Wee1 inhibition pushes the cells through their cycle before DNA repair, promoting mitotic catastrophe and inducing apoptosis of cancer cells. The resulting impairment of the G2-M checkpoint prevents cancer cells from repairing DNA damage, favoring the enhancement of the effect of the DNA damaging therapy and potentially improving therapeutic outcomes.
Focus on DNA Damage Response
DNA damage response consists of all proteins and processes that ensure that the cell cycle does not progress with damaged DNA. Replication is a highly regulated process that guarantees the faithful duplication of the genome once per cell cycle, and any condition that compromises it is referred to as replication stress. Replication stress, characterized by DNA synthesis slow down and or replication fork stalling, is a major cause of genome instability and is linked to the development of tumor cells. Replication is not present in normal cells and as such targeting DDR offers new opportunities for drug development.
Combining WEE1 and PKMYT1 inhibition
Phase 1/1b research exploring the combination of lunresertib and Debio 0123 in patients with advanced solid tumors will be conducted in a new arm of Repare’s ongoing global MYTHIC study (NCT04855656). Debiopharm and Repare are collaborating with the aim to explore the potential synergy between the two compounds to outsmart hard-to-treat cancers via this synthetic lethality.