期刊
BRITISH JOURNAL OF CANCER
卷 109, 期 9, 页码 2356-2367出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2013.584
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资金
- CR-UK
- EPSRC Cancer Imaging Centre at Imperial College, London
- MRC and Department of Health (England) [C2536/A10337]
- Small Molecule Programme [C37/A9335]
- Medicinal Chemistry Training grant [C21484/A6944]
- Cancer Research UK [12011, 6944, 10337] Funding Source: researchfish
- Medical Research Council [MC_U120081322] Funding Source: researchfish
- MRC [MC_U120081322] Funding Source: UKRI
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 angstrom(2)) 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 shortlived 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.
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