Cdk5 in Oncology: Recent Advances and Future Prospects

Lenjisa, Jimma Likisa; Tadesse, Solomon; Khair, Nishat Zareen; Kumarasiri, Malika; Yu, Mingfeng; Albrecht, Hugo; Milne, Robert W.; Wang, Shudong

doi:10.4155/fmc-2017-0097

Cited by 35 publications

(46 citation statements)

References 134 publications

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“…The initial discovery of cyclin-dependent kinases was in the context of the cell cycle where 'cyclins' were cyclically degraded and includes CDK1, CDK2, CDK4 and CDK6. Since then, further CDK functions have been identified for the transcriptional machinery (CDK7, CDK8, CDK9, CDK12), DNA damage response (CDK12) and in tissue specific functions (CDK5) (Reviewed by Malumbres 2014, Lenjisa et al 2017, Philip et al 2018. Despite these diverse functions, the CDKs are structurally very similar, due to the fact that context-specific cyclins are activated to control each function.…”

Section: The Development Of Cdk Inhibitorsmentioning

confidence: 99%

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

Portman

Alexandrou

Carson

et al. 2019

Endocrine-Related Cancer

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109

121

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Three inhibitors of CDK4/6 kinases were recently FDA approved for use in combination with endocrine therapy, and they significantly increase the progression-free survival of patients with advanced estrogen receptor-positive (ER+) breast cancer in the first-line treatment setting. As the new standard of care in some countries, there is the clinical emergence of patients with breast cancer that is both CDK4/6 inhibitor and endocrine therapy resistant. The strategies to combat these cancers with resistance to multiple treatments are not yet defined and represent the next major clinical challenge in ER+ breast cancer. In this review, we discuss how the molecular landscape of endocrine therapy resistance may affect the response to CDK4/6 inhibitors, and how this intersects with biomarkers of intrinsic insensitivity. We identify the handful of pre-clinical models of acquired resistance to CDK4/6 inhibitors and discuss whether the molecular changes in these models are likely to be relevant or modified in the context of endocrine therapy resistance. Finally, we consider the crucial question of how some of these changes are potentially amenable to therapy.

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Section: The Development Of Cdk Inhibitorsmentioning

confidence: 99%

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

Portman

Alexandrou

Carson

et al. 2019

Endocrine-Related Cancer

Self Cite

109

121

View full text Add to dashboard Cite

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“…CDK5 has also been identified to play important roles in processes such as cell death and proliferation, angiogenesis, migration of epithelial and cancer cells, inflammation, myogenesis, glucose metabolism, and insulin secretion in non-neuronal cells [53,87,[89][90][91][92]. These studies have investigated CDK5 function in cells such as cells of hematopoietic lineage, HEK293, COS7, MEF, HCT116, HeLa, adipoctyes, pancreatic β cells, and many other non-neuronal cell types [53,91].…”

Section: Function Of Cdk5 In Non-neuronal Cellsmentioning

confidence: 99%

“…Therefore, more follow-up studies should focus on the effect of stress on CDK5 phosphorylation and solubility and determine whether Noxa or any other apoptotic protein is phosphorylated on serine-13 in lymphoid cells. CDK5 knockdown or inhibition has been documented to be an anticancer agent since and is generally dysregulated in various cancer cells [92].…”

Section: Function Of Cdk5 In Non-neuronal Cellsmentioning

confidence: 99%

CDK5: Key Regulator of Apoptosis and Cell Survival

Roufayel

Murshid

2019

Biomedicines

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The atypical cyclin-dependent kinase 5 (CDK5) is considered as a neuron-specific kinase that plays important roles in many cellular functions including cell motility and survival. The activation of CDK5 is dependent on interaction with its activator p35, p39, or p25. These activators share a CDK5-binding domain and form a tertiary structure similar to that of cyclins. Upon activation, CDK5/p35 complexes localize primarily in the plasma membrane, cytosol, and perinuclear region. Although other CDKs are activated by cyclins, binding of cyclin D and E showed no effect on CDK5 activation. However, it has been shown that CDK5 can be activated by cyclin I, which results in anti-apoptotic functions due to the increased expression of Bcl-2 family proteins. Treatment with the CDK5 inhibitor roscovitine sensitizes cells to heat-induced apoptosis and its phosphorylation, which results in prevention of the apoptotic protein functions. Here, we highlight the regulatory mechanisms of CDK5 and its roles in cellular processes such as gene regulation, cell survival, and apoptosis.

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“…CDK5 has long been considered a relevant pharmacological target in neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's, ALS) and has more recently become an attractive drug target for cancer therapy (Cheung and Ip, 2012;Pozo and Bibb, 2017;Shupp et al, 2017). Aberrant expression or hyperactivation of this kinase contributes to tumorigenesis and progression of several tumors including cancer stem cells by stimulating proliferation, migration, angiogenesis, and CDK5 activity regulates the DNA damage pathway, chemotherapy resistance and anti-tumor immunity (Lenjisa et al, 2017;Pozo and Bibb, 2017;Shupp et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Identification of Quinazolinone Analogs Targeting CDK5 Kinase Activity and Glioblastoma Cell Proliferation

et al. 2020

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CDK5/p25 kinase plays a major role in neuronal functions, and is hyperactivated in several human cancers including glioblastoma and neurodegenerative pathologies such as Alzheimer's and Parkinson's. CDK5 therefore constitutes an attractive pharmacological target. Since the successful discovery and development of Roscovitine, several ATP-competitive inhibitors of CDK5 and peptide inhibitors of CDK5/p25 interface have been developed. However, these compounds suffer limitations associated with their mechanism of action and nature, thereby calling for alternative targeting strategies. To date, few allosteric inhibitors have been developed for successful targeting of protein kinases. Indeed, although this latter class of inhibitors are believed to be more selective than compounds targeting the active site, they have proven extremely difficult to identify in high throughput screens. By implementing a fluorescent biosensor that discriminates against ATP-pocket binding compounds to screen for allosteric inhibitors that target conformational activation of CDK5, we have identified a novel family of quinazolinones. Characterization of these hits and several of their derivatives revealed their inhibitory potential toward CDK5 kinase activity in vitro and to inhibit glioblastoma cell proliferation. The quinazolinone derivatives described in this study are the first small molecules reported to target CDK5 at a site other than the ATP pocket, thereby constituting attractive leads for glioblastoma therapeutics and providing therapeutic perspectives for neurodegenerative diseases. These compounds offer alternatives to conventional ATP-competitive inhibitors or peptides targeting CDK5/p25 interface with the potential of bypassing their limitations.

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Cdk5 in Oncology: Recent Advances and Future Prospects

Cited by 35 publications

References 134 publications

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

CDK5: Key Regulator of Apoptosis and Cell Survival

Identification of Quinazolinone Analogs Targeting CDK5 Kinase Activity and Glioblastoma Cell Proliferation

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