Medicinal chemistry insights into novel CDC25 inhibitors

Tao, Yucen; Hao, Xia; Ding, Xiao; Cherukupalli, Srinivasulu; Song, Yuning; Liu, Xinyong; Zhan, Peng

doi:10.1016/j.ejmech.2020.112374

Cited by 17 publications

(11 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, studies of liver cancer and cervical cancer have indicated that a low level of miR513c-5p expression is related to higher rates of local tissue invasion, lymphatic metastasis, and distant metastasis. 14,39,40 In summary, the miR513c-5p/CDK5/CDC25B axis in TSCC cells may be highly regulated. As an oncogene, CDK5 drives the occurrence and development of TSCC tumors and might serve as a biomarker for diagnosing TSCC and a molecular target for treating the disease.…”

Section: Discussionmentioning

confidence: 91%

“…Few studies have investigated the miR513c‐5p gene, which is upstream of CDK5. However, studies of liver cancer and cervical cancer have indicated that a low level of miR513c‐5p expression is related to higher rates of local tissue invasion, lymphatic metastasis, and distant metastasis 14,39,40 …”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that an increased level of CDK5 target protein is a specific biomarker for cancer and is essential for regulating the growth and migration of tumor cells 8‐13 . There are 3 members of the cell division cycle 25 (CDC25) protein family, namely, CDC25A, CDC25B, and CDC25C, all of which are directly or indirectly involved in the transition of cells in G1/S, S, and G2/M phases and in controlling mitosis 14‐16 . MicroRNA 513c‐5p (miR513c‐5p) is a newly discovered microRNA (miRNA) that is associated with tumorigenesis and development.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cyclin‐dependent kinase 5 promotes the growth of tongue squamous cell carcinoma through the microRNA 513c‐5p/cell division cycle 25B pathway and is associated with a poor prognosis

Fan

Jiao

et al. 2022

Cancer

View full text Add to dashboard Cite

BACKGROUND:The objective of this study was to investigate the role and molecular mechanism of cyclin-dependent kinase 5 (CDK5) in regulating the growth of tongue squamous cell carcinoma (TSCC). METHODS: The authors used multiple methods to detect the levels of CDK5 expression in samples of TSCC and to explore the relation between CDK5 expression and various clinicopathologic factors. In vivo and in vitro cell experiments were performed to detect the proliferation, invasion, and migration of TSCC cells with CDK5 knockdown or overexpression. These studies verified that CDK5 regulates the occurrence and development of TSCC cells through the microRNA 513c-5p/cell division cycle 25B pathway. RESULTS: An elevated level of CDK5 expression in TSCC tissues was identified as an independent risk factor affecting TSCC growth and patient prognosis. Patients who had TSCC with low levels of CDK5 expression had a higher survival rate than those with high levels. Knockdown of CDK5 reduced the proliferation, migration, and invasion of TSCC cells both in vitro and in vivo. In addition, the authors observed that CDK5 regulated the growth of TSCC through the microRNA 513c-5p/cell division cycle C25B pathway. CONCLUSIONS: CDK5 functions as an oncogene in TSCC and might serve as a molecular marker for use in the diagnosis and treatment of TSCC.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cyclin‐dependent kinase 5 promotes the growth of tongue squamous cell carcinoma through the microRNA 513c‐5p/cell division cycle 25B pathway and is associated with a poor prognosis

Fan

Jiao

et al. 2022

Cancer

View full text Add to dashboard Cite

show abstract

“…Given the physiological role played by CDC25 phosphatases in the cell cycle and their involvement in human diseases, a number of laboratories have engaged in drug discovery programs aimed at identifying specific CDC25 inhibitors. − Tao et al summarized the approaches so far adopted to discover CDC25 inhibitors in a recent review . Most compounds so far identified failed to keep up with the expectations, either due to rapid metabolism in tumor-bearing SCID mice or for not completing clinical trials .…”

Section: Introductionmentioning

confidence: 99%

“…12−19 Tao et al summarized the approaches so far adopted to discover CDC25 inhibitors in a recent review. 20 compounds so far identified failed to keep up with the expectations, either due to rapid metabolism in tumor-bearing SCID mice 21 or for not completing clinical trials. 22 Of note, a recent pharmacophore-guided drug discovery program identified naphthoquinone compounds displaying excellent inhibition of CDC25 in enzymatic and cellular assays.…”

Section: ■ Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Metallocene-Tethered Peptidyl Inhibitors of CDC25

et al. 2021

View full text Add to dashboard Cite

Using the pioneering concept developed by Jaouen, Brocard, and co-workers on the replacement of an organic moiety of a known drug by a ferrocenyl unit, we developed organometalliccontaining peptides as inhibitors of dual-specificity phosphatases, cell division cycle 25 (CDC25). More precisely, we designed and prepared the first organometallic-containing CDC25 inhibitors based on the lead structure of an organic pentapeptide inhibitor. Extensive (bio)chemical studies were then undertaken. We first determined that the ferrocene-and CpMn(CO) 3 -containing compounds were unstable in aqueous media, while the ruthenocene and CpRe(CO) 3 derivatives displayed robust stability. All peptidyl compounds were found to effectively inhibit the enzymatic activity of purified CDC25 phosphatases in a dose-dependent manner, with the ruthenocene derivative (3) being the most potent of the series. Low doses of 3 could partially prevent CDC25-mediated dephosphorylation of its physiological target CDK1 when ex vivo studies were conducted on cellular extracts containing endogenous and exogenously supplemented CDC25. Unfortunately, cellular studies to assess the overall cytotoxicity of the peptidyl inhibitors as well as specific effects on cell cycle perturbance, such as arrest at checkpoints that depend on CDC25 activity, were unsuccessful, even when compound shuttling to the cell interior was facilitated by a cell-penetrating carrier peptide. A low cellular uptake of the peptides, as determined by inductively coupled plasma mass spectrometry (ICP-MS), was found to be responsible for this result. However, taking into account the observed enzyme inhibition with our organometallic-containing peptides, this study demonstrates the validity of such an approach and paves the way for future studies in this direction.

show abstract

Discovery of potent and selective Cdc25 phosphatase inhibitors via rapid assembly and in situ screening of Quinonoid-focused libraries

Tao

Hao

Jing

et al. 2021

Bioorganic Chemistry

View full text Add to dashboard Cite

Medicinal chemistry insights into novel CDC25 inhibitors

Cited by 17 publications

References 100 publications

Cyclin‐dependent kinase 5 promotes the growth of tongue squamous cell carcinoma through the microRNA 513c‐5p/cell division cycle 25B pathway and is associated with a poor prognosis

Cyclin‐dependent kinase 5 promotes the growth of tongue squamous cell carcinoma through the microRNA 513c‐5p/cell division cycle 25B pathway and is associated with a poor prognosis

Synthesis and Biological Evaluation of Metallocene-Tethered Peptidyl Inhibitors of CDC25

Discovery of potent and selective Cdc25 phosphatase inhibitors via rapid assembly and in situ screening of Quinonoid-focused libraries

Contact Info

Product

Resources

About