Imperial College London


Faculty of MedicineDepartment of Surgery & Cancer




+44 (0)20 3313 3759eric.aboagye




Mrs Maureen Francis +44 (0)20 7594 2793




GN1Commonwealth BuildingHammersmith Campus






BibTex format

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 = {},
volume = {109},
year = {2013}

RIS format (EndNote, RefMan)

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 -
UR -
VL - 109
ER -