Debio 0123
Debio 0123 is a brain-penetrant, highly selective WEE1 kinase inhibitor. WEE1 is a key regulator of the G2/M and S phase checkpoints, activated in response to DNA damage, allowing cells to repair their DNA before resuming their cell cycle. WEE1 inhibition, particularly in combination with DNA damaging agents, induces an overload of DNA breaks. In conjunction with abrogation of other checkpoints such as G1, the compound pushes the cells through cell cycle without DNA repair, promoting mitotic catastrophe and inducing apoptosis of cancer cells. Debio 0123 is currently in Phase 1/2 clinical research as monotherapy and in combination with different agents. It is being developed to respond to the high unmet needs of patients living with the burden of difficult-to-treat cancers.
Product Snapshot
Inhibition of Wee1 Kinase
Forced arrest of DDR leading to apoptosis
Being researched in:
- Solid tumors
- Small Cell Lung Cancer
- Glioblastoma
In short
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 Ph 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.
About Glioblastoma
Glioblastomas are fast-growing and aggressive brain tumors that can arise de novo or evolve from lower grade gliomas. GBM may be asymptomatic until it reaches a significant size. Aside from diagnostic challenges, nearly all GBM recurs, and effective treatment options are limited. The widely accepted SOC for patients with newly diagnosed GBMs consists of surgical resection, followed by radiation therapy with concurrent TMZ. Despite treatment, nearly all GBM recur, the 5-year survival rate is still only less than 10% [1] and treatment options are very limited.
[1] National Brain Tumor Society. About Glioblastoma. https://doi.org/10.1038/s41419-022-05271-0
About Small Cell Lung Cancer (SCLC)
Lung cancer is the leading cause of cancer mortality worldwide with a yearly estimate of 2.2 million new cases and 1.8 million deaths globally in 2020.[1] SCLC is more prevalent in men over 70 years of age, however the proportion of cases of women has risen over the past 50 years due to a popularization of tobacco consumption.[1] SCLC, an aggressive high-grade malignant epithelial tumor, is deadly, highly metastatic, and highly mutagenic.[1] Because of these traits and despite 30 years of clinical trials designed to improve therapies for SCLC, the outcomes for this disease still remain poor with a median overall survival from diagnosis of up to 13 months in patients receiving standard of care.[2]
[1] Leiter, A., Veluswamy, R.R. & Wisnivesky, J.P. The global burden of lung cancer: current status and future trends. Nat Rev Clin Oncol 20, 624–639 (2023). https://doi.org/10.1038/s41571-023-00798-3
[2] Paz-Ares, Luis et al. “Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.” Lancet (London, England) vol. 394,10212 (2019): 1929-1939. doi:10.1016/S0140-6736(19)32222-6
Clinical trials
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.
Development milestones
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2017
In-licenced by Debiopharm
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2019
Phase 1 combination with carboplatin
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2021
Phase 1 monotherapy trial
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2022
Initial Phase 1 results combination with carboplatin
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2023
Phase 1 glioblastoma and small cell lung cancer trials