Imperial College London
Alternate

ProfessorSimakAli

Faculty of Medicine, Department of Surgery & Cancer

Professor of Molecular Endocrine Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2811simak.ali

 
 
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Location

 

133ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Kaliszczak:2013:10.1038/bjc.2013.584,
author = {Kaliszczak, M and Patel, H and Kroll, SHB and Carroll, L and Smith, G and Delaney, S and Heathcote, DA and Bondke, A and Fuchter, MJ and Coombes, RC and Barrett, AGM and Ali, S and Aboagye, EO},
doi = {10.1038/bjc.2013.584},
journal = {British Journal of Cancer},
pages = {2356--2367},
title = {Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance},
url = {http://dx.doi.org/10.1038/bjc.2013.584},
volume = {109},
year = {2013}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Kaliszczak,M
AU  - Patel,H
AU  - Kroll,SHB
AU  - Carroll,L
AU  - Smith,G
AU  - Delaney,S
AU  - Heathcote,DA
AU  - Bondke,A
AU  - Fuchter,MJ
AU  - Coombes,RC
AU  - Barrett,AGM
AU  - Ali,S
AU  - Aboagye,EO
DO  - 10.1038/bjc.2013.584
EP  - 2367
PY  - 2013///
SN  - 1532-1827
SP  - 2356
TI  - Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance
T2  - British Journal of Cancer
UR  - http://dx.doi.org/10.1038/bjc.2013.584
UR  - http://hdl.handle.net/10044/1/33463
VL  - 109
ER  -
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