Investigational drugs targeting cyclin-dependent kinases for the treatment of cancer: an update on recent findings (2013-2016).
BACKGROUND
Cell cycle and gene transcription are under the control of cyclin-dependent kinases (CDKs), whose activity depends on the binding with cyclins. Deregulated CDK activities have been reported in a majority of human cancers, representing potential therapeutic targets.


METHODS
This review provides preclinical and clinical (phase I/II) updates of promising therapeutic compounds targeting CDKs published between 2013 and 2016 EXPERT OPINION: First generation pan-CDK inhibitors showed marked toxicity in clinical trials and most compounds were discontinued. Despite their failure was ascribed also to inadequate patient selection rules, novel pan-CDK inhibitors have entered clinical trials with still poorly defined selection strategies. The most interesting results have been obtained with dual CDK4/6 inhibitors and through a more accurate evaluation of predictive biomarkers, suggesting the usefulness of CDK inhibitors for personalized treatment. The increased knowledge on the roles of CDKs in cell cycle and gene transcription suggests to review also the anticancer potential of first generation CDK inhibitors by defining more appropriate rules for patients engagement. Recent findings has highlighted CDK8 as a novel target for cancer treatment. Indeed some biomarkers for CDK8 inhibition sensitivity have already been proposed. CDK8 inhibition is also supposed to prevent cancer metastasis.
a Department of Pharmacy , University of Naples Federico II , Naples , Italy.
Carmen
C
Di Giovanni
a Department of Pharmacy , University of Naples Federico II , Naples , Italy.
Ettore
E
Novellino
b Department of Pharmaceutical and Pharmacological Sciences , University of Padova , Padova , Italy.
Adriana
A
Chilin
a Department of Pharmacy , University of Naples Federico II , Naples , Italy.
Antonio
A
Lavecchia
b Department of Pharmaceutical and Pharmacological Sciences , University of Padova , Padova , Italy.
Giovanni
G
Marzaro
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D015195:Drug Design; D015507:Drugs, Investigational / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018579:Patient Selection; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D047428:Protein Kinase Inhibitors; D018844:Cyclin-Dependent Kinases
CDK selective inhibitors; CDK8 inhibitors; Cyclin-dependent kinases (CDKs); cancer; clinical trial