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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance

M Kaliszczak1, H Patel, S H B Kroll

  • 1Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.

British Journal of Cancer
|September 28, 2013
PubMed
Abstract

Insights

Researchers developed a new anticancer drug, ICEC-0782, that targets cyclin-dependent kinases (CDKs) and overcomes drug resistance. This novel compound effectively inhibits tumor growth in preclinical models and is suitable for further clinical evaluation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cyclin-dependent kinases (CDKs) are crucial regulators of cell cycle, transcription, and apoptosis, making them key targets for cancer therapy.
  • Existing CDK inhibitors show limited efficacy, necessitating the development of more effective agents.
  • Drug resistance, often mediated by ATP-binding cassette (ABC) transporters, poses a significant challenge in cancer treatment.

Purpose of the Study:

  • To develop novel pyrazolo[1,5-a]pyrimidine compounds with improved efficacy against cancer.
  • To identify structural features that confer resistance to ABC transporter-mediated drug efflux.
  • To evaluate a lead compound, ICEC-0782, for its preclinical anticancer activity and drug resistance profile.

Main Methods:

  • Generated drug-resistant cell lines via continuous exposure to a model CDK inhibitor.
  • Investigated structural determinants of ABC transporter interaction, identifying high polar surface area as a key factor.
  • Synthesized and characterized ICEC-0782, a novel CDK inhibitor with preferential activity against CDK2, CDK7, and CDK9.
  • Assessed ICEC-0782's effects on CDK substrate phosphorylation, short-lived protein levels, cell cycle progression, and apoptosis.
  • Evaluated ICEC-0782's efficacy in vivo using human colon (HCT-116) and breast (MCF7) tumor xenograft models.

Main Results:

  • Drug-resistant cells exhibited induced expression of ABC transporters ABCB1 and ABCG2.
  • High polar surface area (>100 Ų) was identified as a critical determinant for ABC transporter substrate interaction.
  • ICEC-0782 demonstrated potent inhibition of CDK2, CDK7, and CDK9 in the nanomolar range.
  • ICEC-0782 effectively inhibited CDK substrate phosphorylation, downregulated Mcl-1 and cyclin D1, induced G2/M arrest, and promoted apoptosis.
  • ICEC-0782's permeability and cytotoxicity were independent of ABC transporter expression.
  • In vivo, ICEC-0782 achieved significant tumor growth inhibition (84% for HCT-116, 94% for MCF7) following daily oral administration.

Conclusions:

  • A novel pyrazolo[1,5-a]pyrimidine compound, ICEC-0782, was developed with potent CDK inhibitory activity.
  • ICEC-0782 is not a substrate for ABC transporters, overcoming a common mechanism of drug resistance.
  • ICEC-0782 exhibits significant preclinical efficacy in vitro and in vivo, demonstrating its potential for cancer treatment.
  • ICEC-0782 is a promising candidate for further preclinical and clinical development in oncology.

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