(Health Korea News / Lee Chung-man) Protein kinase 1 (WEE1) inhibitors are gaining attention as next-generation anticancer drugs as it has been confirmed that they can be used across a wide range of cancer types.
The cell division cycle is the series of stages a cell goes through when dividing, divided into the G1, S, G2, and M phases. Each stage is a checkpoint in the middle of the process to ensure that the DNA has been properly repaired before the cell moves on to the next stage.
A protein called WEE1 plays a key role at the G2 and M checkpoints. This protein stops cells from dividing directly from G2 to M phase, but instead pauses for a moment. This allows cells time to repair DNA damage at the G2/M checkpoint.
The mechanism of action of WEE1 is to regulate CDK1 protein activity. When CDK1 is activated, cells begin to divide, and WEE1 can inhibit CDK1 activity by adding a phosphate group to the tyrosine 15 amino acid of CDK1, causing a chemical change (phosphorylation).
The industry has begun developing new anticancer drugs that inhibit WEE1 based on the fact that WEE1 is involved in DNA repair during cell division. In particular, WEE1 inhibitors are expected to show promising therapeutic effects in p53-mutated cancers.
p53 is a protein that intervenes at the G1 and S checkpoints during the cell division cycle. A healthy p53 protein, like the WEE1 protein, stops the division process when DNA damage is detected at the G1 checkpoint, allowing time for the damage to be repaired. As a result, cells become more dependent on the G2 and M checkpoints.
At this time, if even WEE1, which is involved in the G2·M checkpoint, is inhibited by a WEE1 inhibitor, the cell will divide without being able to repair DNA, leading to cell death due to synthetic lethality.
When this is applied to cancer cells, p53 mutant cancer cells are highly dependent on the WEE1 protein at the G2·M checkpoint, so it is expected that using a WEE1 inhibitor will prevent DNA damage from being repaired even at the G2·M checkpoint, leading to cancer cell death and cancer treatment.
In addition, p53 mutations occur in almost all types of cancer at a rate of about 5%, and are known to account for 40-50% of ovarian cancer, esophageal cancer, colon cancer, head and neck cancer, and laryngeal cancer that do not respond well to immunotherapy. For this reason, WEE1 inhibitors are attracting attention as next-generation anticancer agents.
According to our investigation, there are currently 19 WEE1 inhibitors under development worldwide.
(Current status of WEE1 inhibitor development)
|
Item |
enterprise |
Development stage |
|
SC0191 |
Hongren, Jijiang, Shijiazhuang, China(Shijiazhuang Zhikang Hongren) |
Clinical 2Upper test |
|
Azenosertip(azenosertib) |
US Zentalis Pharmaceuticals(Zentalis Pharmaceuticals) |
Clinical 2Upper test |
|
Adaboservtip(adavosertib) |
USA MSD·AstraZeneca UK(Astrazeneca, AZ) |
Clinical 2Upper test |
|
Debio-0123 |
Swiss Debiopharm(Debiopharm) |
Clinical 1/2Upper test |
|
Portrace Tips(potrasertib) |
China Impact Therapeutics(IMPACT Therapeutics) |
Clinical 1Upper test |
|
SGR-3515 |
American Schrodinger(Schrödinger) |
Clinical 1Upper test |
|
SY-4835 |
China Shoyao Holdings(Shouyao Holdings) |
Clinical 1Upper test |
|
Apr-1051 |
Aprea Therapeutics, USA(Aprea Therapeutics) |
Clinical 1Upper test |
|
Unknown |
China Pharmaceutical University(China Pharmaceutical University) |
Preclinical trials |
|
DN-1609 |
China Pistek(Piistech) |
Preclinical trials |
|
ML118 |
American Script Institute(The Scripps Research Institute) |
Preclinical trials |
|
ZNL-02-096 |
Dana-Farber Cancer Institute, USA(Dana-Farber Cancer Institute) |
Preclinical trials |
|
ACR-2316 |
Acribon Therapeutics, USA(Acrivon Therapeutics) |
Preclinical trials |
|
SPH-6162 |
Shanghai Pharmaceuticals, China(Shanghai Pharmaceuticals) |
Preclinical trials |
|
HGC-230 |
China Tasli Pharmaceuticals(Tasly Pharmaceuticals) |
Preclinical trials |
|
SID-415260 |
USA MSD |
Preclinical trials |
|
Unknown |
China Chia Tai Tianqing Pharmaceuticals(Chia Tai Tianqing Pharmaceutical) |
Preclinical trials |
|
Unknown |
China Degron Therapeutics(Degron Therapeutics) |
drug discovery |
|
PD-0166285 |
Pfizer USA(Pfizer) |
drug discovery |
The leaders in development are ▲’SC0191′ by Shijiazhuang Zhikang Hongren of China ▲’azenosertib’ by Zentalis Pharmaceuticals of the US ▲’adavosertib’ by MSD of the US and AstraZeneca (AZ) of the UK, which are currently being evaluated in phase 2.
Among them, Zentalis’ ‘Azenosertib’ recently had its partial clinical trial hold lifted, freeing the shackles on new drug development.
The U.S. Food and Drug Administration (FDA) placed three clinical trials on partial hold in June of this year after two patients who received azenosertib died of sepsis. The trials were Phase 1 for solid tumor patients and Phase 2 for ovarian and uterine cancer. The two deceased patients were participants in the ovarian cancer clinical trial.
The FDA lifted the partial hold on three cases on September 16 (local time), about three months later. According to Zentalis, the FDA allowed patient enrollment in three ongoing clinical trials without any changes to the clinical design.
Zentalis plans to work with clinical investigators to resume trials of azenosertib as soon as possible.
The pharmaceutical and biotechnology industry expects that if WEE1 inhibitors successfully complete phase 2 clinical trials, the era of multi-target anticancer drugs that can be used for all cancer types will quickly approach.
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Source: www.hkn24.com
