Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance

M. Kaliszczak, H. Patel, S. H.B. Kroll, Laurence Carroll, G. Smith, S. Delaney, D. A. Heathcote, A. Bondke, M. J. Fuchter, R. C. Coombes, A. G.M. Barrett, S. Ali, E. O. Aboagye

Research output: Contribution to journalArticle

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 Å 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 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.

Original languageEnglish (US)
Pages (from-to)2356-2367
Number of pages12
JournalBritish Journal of Cancer
Volume109
Issue number9
DOIs
StatePublished - Oct 29 2013
Externally publishedYes

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ATP-Binding Cassette Transporters
Cyclin-Dependent Kinases
Drug Resistance
Apoptosis
Cyclin D1
Substrate Specificity
Cell Cycle Checkpoints
Heterografts
Pharmaceutical Preparations
Libraries
Permeability
Colon
Down-Regulation
Phosphorylation
RNA
Breast Neoplasms
Growth
Neoplasms
Proteins
pyrazolo(1,5-a)pyrimidine

Keywords

  • biomarkers
  • CDK
  • MDR
  • pharmacology
  • tumour

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kaliszczak, M., Patel, H., Kroll, S. H. B., Carroll, L., Smith, G., Delaney, S., ... Aboagye, E. O. (2013). Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance. British Journal of Cancer, 109(9), 2356-2367. https://doi.org/10.1038/bjc.2013.584

Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance. / Kaliszczak, M.; Patel, H.; Kroll, S. H.B.; Carroll, Laurence; Smith, G.; Delaney, S.; Heathcote, D. A.; Bondke, A.; Fuchter, M. J.; Coombes, R. C.; Barrett, A. G.M.; Ali, S.; Aboagye, E. O.

In: British Journal of Cancer, Vol. 109, No. 9, 29.10.2013, p. 2356-2367.

Research output: Contribution to journalArticle

Kaliszczak, M, Patel, H, Kroll, SHB, Carroll, L, Smith, G, Delaney, S, Heathcote, DA, Bondke, A, Fuchter, MJ, Coombes, RC, Barrett, AGM, Ali, S & Aboagye, EO 2013, 'Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance', British Journal of Cancer, vol. 109, no. 9, pp. 2356-2367. https://doi.org/10.1038/bjc.2013.584
Kaliszczak, M. ; Patel, H. ; Kroll, S. H.B. ; Carroll, Laurence ; Smith, G. ; Delaney, S. ; Heathcote, D. A. ; Bondke, A. ; Fuchter, M. J. ; Coombes, R. C. ; Barrett, A. G.M. ; Ali, S. ; Aboagye, E. O. / Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance. In: British Journal of Cancer. 2013 ; Vol. 109, No. 9. pp. 2356-2367.
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AU - Smith, G.

AU - Delaney, S.

AU - Heathcote, D. A.

AU - Bondke, A.

AU - Fuchter, M. J.

AU - Coombes, R. C.

AU - Barrett, A. G.M.

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