Inhibitors of cell cycle checkpoint target Wee1 kinase – a patent review (2003–2022)

Yan, Jingxue; Zhuang, Lili; Wang, Yong; Jiang, Yiqing; Tu, Zhenlin; Dong, Chao; Chen, Yadong; Zhu, Yong

doi:10.1080/13543776.2022.2166827

Cited by 7 publications

(4 citation statements)

References 60 publications

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“…In contrast, genes Wee1 (UV8b_00129) encoding mitosis inhibitor protein kinase and asp1 (UV8b_01110) encoding inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase were downregulated 2.06- and 2.70-fold, respectively. Wee1 is a key kinase at the G2/M checkpoint of the cell cycle and plays a key role in cell cycle regulation and DNA damage repairment . Asp1 has been identified to regulate numerous cellular processes, including the dynamics of the microtubule cytoskeleton in interphase cells, spindle assembly, and dynamics and correct association of spindle microtubules .…”

Section: Resultsmentioning

confidence: 99%

“…Wee1 is a key kinase at the G2/M checkpoint of the cell cycle and plays a key role in cell cycle regulation and DNA damage repairment. 38 Asp1 has been identified to regulate numerous cellular processes, including the dynamics of the microtubule cytoskeleton in interphase cells, spindle assembly, and dynamics and correct association of spindle microtubules. 39 The downregulation of Wee1 and slp1 indicated that 2,4-DTBP could induce U. virens mitotic catastrophe, consequently resulting in cell death.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

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Antifungal Activity and Action Mechanisms of 2,4-Di-tert-butylphenol against Ustilaginoidea virens

Fan,

Yu,

et al. 2023

J. Agric. Food Chem.

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Ustilaginoidea virens is a destructive phytopathogenic fungus that causes false smut disease in rice. In this study, the natural product 2,4-di-tert-butylphenol (2,4-DTBP) was found to be an environmentally friendly and effective agent for the first time, which exhibited strong antifungal activity against U. virens, with an EC50 value of 0.087 mmol/L. The scanning electron microscopy, fluorescence staining, and biochemical assays indicated that 2,4-DTBP could destroy the cell wall, cell membrane, and cellular redox homeostasis of U. virens, ultimately resulting in fungal cell death. Through the transcriptomic analysis, a total of 353 genes were significantly upregulated and 367 genes were significantly downregulated, focusing on the spindle microtubule assembly, cell wall and membrane, redox homeostasis, mycotoxin biosynthesis, and intracellular metabolism. These results enhanced the understanding of the antifungal activity and action mechanisms of 2,4-DTBP against U. virens, supporting it to be a potential antifungal agent for the control of false smut disease.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Materials and Methodsmentioning

confidence: 99%

Antifungal Activity and Action Mechanisms of 2,4-Di-tert-butylphenol against Ustilaginoidea virens

Fan,

Yu,

et al. 2023

J. Agric. Food Chem.

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“…WEE1 also protects replication forks and inhibition of WEE1 can induce the uncontrolled firing of replication origins, leading to increased replication stress [112,113]. Given these effects, several WEE1 inhibitors (Figure 1 and Table 1) have been developed with a focus on engineering synthetic lethality by using WEE1 inhibitors in combination with DNA-damaging chemotherapies or radiation [114,115]. Importantly, greater than 50% of all human cancers harbor mutations in the tumor suppressor gene p53, which plays a major role in genomic stability by transcriptionally regulating downstream genes involved in the G1/S checkpoint in response to DNA damage [116].…”

Section: Inhibiting Wee1mentioning

confidence: 99%

Therapeutic Targeting of DNA Replication Stress in Cancer

Hickey

Malkas

2023

Genes

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This article reviews the currently used therapeutic strategies to target DNA replication stress for cancer treatment in the clinic, highlighting their effectiveness and limitations due to toxicity and drug resistance. Cancer cells experience enhanced spontaneous DNA damage due to compromised DNA replication machinery, elevated levels of reactive oxygen species, loss of tumor suppressor genes, and/or constitutive activation of oncogenes. Consequently, these cells are addicted to DNA damage response signaling pathways and repair machinery to maintain genome stability and support survival and proliferation. Chemotherapeutic drugs exploit this genetic instability by inducing additional DNA damage to overwhelm the repair system in cancer cells. However, the clinical use of DNA-damaging agents is limited by their toxicity and drug resistance often arises. To address these issues, the article discusses a potential strategy to target the cancer-associated isoform of proliferating cell nuclear antigen (caPCNA), which plays a central role in the DNA replication and damage response network. Small molecule and peptide agents that specifically target caPCNA can selectively target cancer cells without significant toxicity to normal cells or experimental animals.

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“…It received orphan drug designation for the treatment of osteosarcoma and rare pediatric disease designation for the same indication in 2021 and is undergoing phase II clinical evaluation as a single-agent treatment for locally advanced or metastatic solid tumors including recurrent or persistent uterine serous carcinoma . Other inhibitors such as IMP7068, Debio-0123, SC0191, and SY-4835 (Figure ) are currently in phase I clinical trials, while several small molecule inhibitors ,− and degraders − are still in preclinical stages.…”

Section: Introductionmentioning

confidence: 99%

Advanced Design, Synthesis, and Evaluation of Highly Selective Wee1 Inhibitors: Enhancing Pharmacokinetics and Antitumor Efficacy

Wang,

Xu,

Jiang

et al. 2024

J. Med. Chem.

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Wee1 is a kinase that regulates cell cycle arrest in response to DNA damage. Wee1 inhibition is a potential strategy to suppress the growth of tumors with defective p53 or DNA repair pathways. However, the development of Wee1 inhibitors faces some challenges. AZD1775, the first-in-class Wee1 inhibitor, has poor kinase selectivity and dose-limiting toxicity. Here, we report the discovery of 12h, a highly selective and potent Wee1 inhibitor with a favorable pharmacokinetic profile. 12h showed strong antiproliferative effects against Lovo cells, a colorectal cancer cell line, both in vitro and in vivo. Moreover, 12h showed a clean kinase profile and effectively induced cell apoptosis. Our results suggest that 12h is a promising drug candidate for further development as a novel anticancer agent.

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Inhibitors of cell cycle checkpoint target Wee1 kinase – a patent review (2003–2022)

Cited by 7 publications

References 60 publications

Antifungal Activity and Action Mechanisms of 2,4-Di-tert-butylphenol against Ustilaginoidea virens

Antifungal Activity and Action Mechanisms of 2,4-Di-tert-butylphenol against Ustilaginoidea virens

Therapeutic Targeting of DNA Replication Stress in Cancer

Advanced Design, Synthesis, and Evaluation of Highly Selective Wee1 Inhibitors: Enhancing Pharmacokinetics and Antitumor Efficacy

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