Kinase Inhibitors

Altered phosphorylation of cellular proteins in cancer cells stimulated an extensive search for protein kinase inhibitors as a new generation of chemotherapeutics. Cyclin-dependent kinases (CDK) are enzymes involved in diverse cellular processes such as the cell division cycle, transcription, differentiation and apoptosis, and thus are suitable targets for such inhibitors with potential pharmacological applications.

The identification of the 2,6,9-trisubstituted purine olomoucine as a moderately potent inhibitor of CDKs initiated an inhibitor development program in many labs. Structural modifications of olomoucine culminated in the syntheses of improved inhibitors such as roscovitine, bohemine and olomoucine II. All novel derivatives display an enhanced CDK inhibitory activity, increased enzyme selectivity and antiproliferative activity. A significant correlation between CDK inhibitory activity of 2,6,9-trisubstituted purines and their in vitro anticancer activity further confirms their potential clinical applications.

In recent years in addition to 2,6,9-trisubstituted purines a number of other pharmacological CDK inhibitors with a wide variety of cellular impacts has been discovered in our laboratory, including pyrazolo[4,3-d]pyrimidines, 8-azapurines and 4-arylazo-3,5-diaminopyrazoles. Their antiproliferative activities are usually connected with specific and potent inhibition of CDKs involved in cell cycle regulation and transcription.

Besides their effect on cell cycle progression, several CDK inhibitors have been shown to induce nuclear accumulation of tumour suppressor protein p53 and to enhance p53-dependent transcription in human cancer cells. This induction of p53 is triggered at least partially by inhibition of CDKs regulating transcription, i.e. CDKs 7, 8 and 9, as demonstrated by experiments with roscovitine and CAN508, inhibiting preferentially CDK9 activity. CDK9, as one of the components of transcription elongation factor P-TEFb, controls the processivity of RNA polymerase II by phosphorylating the carboxy-terminal domain of its largest subunit. The perturbations in RNA synthesis caused by CDK inhibitors II lead to down-regulation of many gene products with short-lived mRNAs and/or proteins, e.g. oncogenic cyclins or anti-apoptotic proteins Mcl-1 and XIAP. Insufficient transcription also activates tumour suppressor p53, which then contributes to antiproliferative properties of the compounds. Especially our recent work, made possible by identification of the highly selective CDK9 4-arylazo-3,5-diaminopyrazole inhibitor, CAN508, suggests that CDK9 inhibitors of transcription could serve as potential drugs against tumor invasion and metastasis, or against some viral infections.

One-day conference:
Protein Kinase Inhibitors: Possible Pharmacological Applications
14. 6. 2010

Group Members
Vladimír Kryštof
Radek Jorda
Iva Dolečková
Eva Řezníčková
Jana Navrátilová
Ladislava Vymětalová