1. Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance.
- Author
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Kaliszczak, M, Patel, H, Kroll, S H B, Carroll, L, Smith, G, Delaney, S, Heathcote, D A, Bondke, A, Fuchter, M J, Coombes, R C, Barrett, A G M, Ali, S, and Aboagye, E O
- Subjects
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CYCLIN-dependent kinase inhibitors , *ATP-binding cassette transporters , *DRUG resistance , *CELL cycle regulation , *GENETIC transcription , *APOPTOSIS - 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]
- Published
- 2013
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