Peptides or small molecules? Different approaches to develop more effective CDK inhibitors

D. Cirillo, F. Pentimalli, A. Giordano

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Cell cycle regulation involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control cell cycle are ordered and directional. Cyclins and cyclin-dependent kinases (CDKs), determine cell progression through the cycle ensuring the orderly coordination of cellular events. Alterations of cell cycle controllers are among the main causes of cancer onset. In the past decades many efforts have been made to develop kinase inhibitors that are able to modulate cyclin and CDK complexes, either by mimicking the function of natural CDK inhibitors, such as p21, p16 and p27, or by modulating the cyclin-CDK complexes or their targets directly. The great debate is whether to use peptides or small molecules. Peptides are more selective being derived by the linear protein sequences, indeed they should mimic the catalytic or the regulatory subunits of the cell cycle controller complexes, but on the other side they usually present poorer pharmacokinetic characteristics. In contrast, small molecules have better pharmacokinetic features but lower specificity because many protein kinases show high sequence similarity within the active site. The purpose of this review article is to provide an overview of the main classes of CDK inhibitors focusing on structure-activity relationship (SAR) studies and discussing the pharmacological and therapeutic implications.

Original languageEnglish
Pages (from-to)2854-2866
Number of pages13
JournalCurrent Medicinal Chemistry
Volume18
Issue number19
DOIs
Publication statusPublished - Jun 2011

Fingerprint

Cyclin-Dependent Kinases
Cells
Cyclins
Peptides
Molecules
Cell Cycle
Pharmacokinetics
Structure-Activity Relationship
Controllers
Cell Cycle Checkpoints
Cell Division
Protein Kinases
Catalytic Domain
Cell Survival
Phosphotransferases
Pharmacology
Repair
Neoplasms
Proteins

Keywords

  • Cancer
  • CDK
  • Kinase inhibitor
  • Peptide
  • SAR
  • Small molecule

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Peptides or small molecules? Different approaches to develop more effective CDK inhibitors. / Cirillo, D.; Pentimalli, F.; Giordano, A.

In: Current Medicinal Chemistry, Vol. 18, No. 19, 06.2011, p. 2854-2866.

Research output: Contribution to journalArticle

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