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Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance.
- Source :
-
British Journal of Cancer . 10/29/2013, Vol. 109 Issue 9, p2356-2367. 12p. - Publication Year :
- 2013
-
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 Å2) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively.Conclusion:We identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00070920
- Volume :
- 109
- Issue :
- 9
- Database :
- Academic Search Index
- Journal :
- British Journal of Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 91696270
- Full Text :
- https://doi.org/10.1038/bjc.2013.584