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Cyclin-Dependent Kinase 5 (CDK5) Controls Melanoma Cell Motility, Invasiveness, and Metastatic Spread-Identification of a Promising Novel therapeutic target.

Bisht S, Nolting J, Schütte U, Haarmann J, Jain P, Shah D, Brossart P, Flaherty P, Feldmann G - Transl Oncol (2015)

Bottom Line: In vivo, CDK5 knockdown inhibited growth of orthotopic xenografts as well as formation of lung and liver colonies in xenogenic injection models mimicking systemic metastases.CDK5 knockdown was accompanied by dephosphorylation and overexpression of caldesmon, and concomitant caldesmon knockdown rescued cell motility and proinvasive phenotype.Finally, it was found that pharmacological inhibition of CDK5 activity by means of roscovitine as well as by a novel small molecule CDK5-inhibitor, N-(5-isopropylthiazol-2-yl)-3-phenylpropanamide, similarly caused marked inhibition of invasion/migration, colony formation, and anchorage-independent growth of melanoma cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Germany.

No MeSH data available.


Related in: MedlinePlus

PJB as small molecule CDK5 inhibitor. (A) Chemical structure of PJB. (B) Kinase assays show dose-dependent inhibition of CDK5 kinase activity by PJB.
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f0035: PJB as small molecule CDK5 inhibitor. (A) Chemical structure of PJB. (B) Kinase assays show dose-dependent inhibition of CDK5 kinase activity by PJB.

Mentions: Having identified CDK5 as a promising molecular target for therapeutic intervention in melanoma using genetic in vitro and in vivo model systems as described above, we next wanted to evaluate if these therapeutic effects could be replicated by pharmacological inhibition of CDK5 as well. To this end, a series of novel small molecule inhibitors was screened for their ability to bind CDK5 and block its kinase activity [30]. N-(5-isopropylthiazol-2-yl)-3-phenylpropanamide (PJB) (Pubchem CID = 16760027) (Figure 7A) was found to potently inhibit CDK5 activity in kinase assays (Figure 7B), which is in line with previous observations, which had shown an IC50 of around 64 nM for CDK5 and 98 nM for CKD2 inhibition, respectively [31,32]. For subsequent efficacy testing, PJB was used alongside the well-established yet less specific small molecule CDK5 inhibitor roscovitine.


Cyclin-Dependent Kinase 5 (CDK5) Controls Melanoma Cell Motility, Invasiveness, and Metastatic Spread-Identification of a Promising Novel therapeutic target.

Bisht S, Nolting J, Schütte U, Haarmann J, Jain P, Shah D, Brossart P, Flaherty P, Feldmann G - Transl Oncol (2015)

PJB as small molecule CDK5 inhibitor. (A) Chemical structure of PJB. (B) Kinase assays show dose-dependent inhibition of CDK5 kinase activity by PJB.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562979&req=5

f0035: PJB as small molecule CDK5 inhibitor. (A) Chemical structure of PJB. (B) Kinase assays show dose-dependent inhibition of CDK5 kinase activity by PJB.
Mentions: Having identified CDK5 as a promising molecular target for therapeutic intervention in melanoma using genetic in vitro and in vivo model systems as described above, we next wanted to evaluate if these therapeutic effects could be replicated by pharmacological inhibition of CDK5 as well. To this end, a series of novel small molecule inhibitors was screened for their ability to bind CDK5 and block its kinase activity [30]. N-(5-isopropylthiazol-2-yl)-3-phenylpropanamide (PJB) (Pubchem CID = 16760027) (Figure 7A) was found to potently inhibit CDK5 activity in kinase assays (Figure 7B), which is in line with previous observations, which had shown an IC50 of around 64 nM for CDK5 and 98 nM for CKD2 inhibition, respectively [31,32]. For subsequent efficacy testing, PJB was used alongside the well-established yet less specific small molecule CDK5 inhibitor roscovitine.

Bottom Line: In vivo, CDK5 knockdown inhibited growth of orthotopic xenografts as well as formation of lung and liver colonies in xenogenic injection models mimicking systemic metastases.CDK5 knockdown was accompanied by dephosphorylation and overexpression of caldesmon, and concomitant caldesmon knockdown rescued cell motility and proinvasive phenotype.Finally, it was found that pharmacological inhibition of CDK5 activity by means of roscovitine as well as by a novel small molecule CDK5-inhibitor, N-(5-isopropylthiazol-2-yl)-3-phenylpropanamide, similarly caused marked inhibition of invasion/migration, colony formation, and anchorage-independent growth of melanoma cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Germany.

No MeSH data available.


Related in: MedlinePlus