Debio 0123, a potent oral WEE1 Inhibitor being developed by Swiss-based biopharmaceutical company Debiopharm, will be assessed in a first-in-human, phase I study. The study includes Debio 0123 in combination with carboplatin in patients with advanced solid tumors.
The dose-escalation trial will be conducted in patients with refractory solid tumors that have recurred or progressed following prior platinum-based chemotherapy and for which no standard treatment is available.
WEE1 inhibitors
WEE1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases and is a key regulator of cell cycle progression (G2 to M transition or G2/M).[1]
Debio 0123
Debio 0123 is one of four WEE1 inhibitors in clinical development. The clinical study is being initiated based on the deepened understanding of the DNA damage response (DDR) of cancer cells.
Initially discovered by Almac Discovery before being licensed by Debiopharm, Debio 0123 has shown anti-tumor activity both as a single agent and in combination with carboplatin in pre-clinical cancer models. The advancement of Debio 0123 into clinical studies may reveal improved therapeutic results for cancer patients.
“This clinical phase of Debio 0123 is highly anticipated in light of the therapeutic potential of the molecule. Pre-clinical research results suggest that this potent WEE-1 inhibitor has the potential to show activity in cancer patients, particularly in combination with DNA damaging treatments, such as chemo- and radiation-therapies” explained Angela Zubel, Chief Development Officer, Debiopharm.
DNA Damage
The DNA in cancer cells can be damaged by a variety of causes, including radiation, antimetabolites, alkylating agents, DNA topoisomerase inhibitors and platinum-based chemotherapy.
This externally caused DNA damage can result in genomic instability, defined as higher than normal rates of mutation, which is recognized as one of the distinguishing characteristics of cancer and is controlled by cell cycle checkpoints.
And both G1 and G2 checkpoints allow DNA damage responses, while the mitotic checkpoint facilitates correct segregation of the sister chromosomes to prevent aneuploidy (the presence of an abnormal number of chromosomes in a cell) [1][2]
When such DNA damage occurs, the cells respond by pausing the cell cycle temporarily to allow for DNA repair. In turn, this reduces the effectiveness of cytotoxic therapies against cancer cells.
However, while healthy, normal, cells repair damaged DNA during G1 arrest, most cancer cells have a deficient G1-S checkpoint and, as a result, lack a functional G1 arrest. They rely on a functional G2-M checkpoint and G2 arrest for DNA damage responses and repair.
Inhibiting DNA Damage Response
The pharmacological control of DNA damage response may be used to directly block tumor growth by hindering cell division and induce apoptosis. It may also indirectly unleash the immune system against tumor cells.
Inhibition of WEE1 forces cells in a state of arrest to continue the cell cycle, ultimately leading to cell death. The resulting impairment of the G2-M checkpoint would prevent cancer cells from repairing induced DNA damage, considerably enhancing the effect of the DNA damaging therapy and thus optimizing the therapeutic outcome.
Treatments such as Debio 0123 which inhibit DNA damage response are promising drug candidates as they can enhance the effects of DNA damaging therapies and, as a result, promote a lethal response.
There is emerging evidence demonstrating that WEE1 has also critical functions as a regulator of the S phase and as an epigenetic modifier. These findings coupled with the frequently observed functional inactivation of p53, which controls G1 cell cycle arrest, suggest that WEE1 inhibitors may have therapeutic benefits across a multitude of cancer types in both combination and monotherapy modalities.
Other WEE1 inhibitors include:
- Adavosertib, also known as AZD1775 or MK-1775, a small-molecule, pyrazolpyrimidine derivative and potent and ATP-competitive specific inhibitor of the WEE1 kinase, being developed by AstraZeneca.
- PD0166285, a ppyrido [2,3-d] pyimidine compound, being developped by Pfizer [4]
- PD0407824, a checkpoint kinase Chk1 and WEE1 inhibitor with IC50s of 47 and 97 nM, respectively, being developped by Pfizer.
Clinical trials
Study of Oral Debio 0123 in Combination With Carboplatin in Participants With Advanced Solid Tumors – NCT03968653.
Reference
[1] Vriend LE, De Witt Hamer PC, Van Noorden CJ, Würdinger T. WEE1 inhibition and genomic instability in cancer. Biochim Biophys Acta. 2013;1836(2):227–235. doi:10.1016/j.bbcan.2013.05.002
[2] Griffiths AJF, Miller JH, Suzuki DT, et al. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000. Aneuploidy. Online. Last accessed March 5, 2020.
[3] Matheson CJ, Backos DS, Reigan P. Targeting WEE1 Kinase in Cancer. Trends Pharmacol Sci. 2016;37(10):872–881. doi:10.1016/j.tips.2016.06.006
[4] Hashimoto O, Ueno T, Kimura R, et al. Inhibition of proteasome-dependent degradation of Wee1 in G2-arrested Hep3B cells by TGF beta 1. Mol Carcinog. 2003;36(4):171–182. doi:10.1002/mc.10111
