Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance.

ABSTRACT:

Background

Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy.

Methods

We generated drug-resistant cells by continuous low-dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy.

Results

We identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 Å(2)) as a key determinant of transporter interaction. We developed

SUBMITTER: Kaliszczak M 

PROVIDER: S-EPMC3817326 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature