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Updated: Feb 16, 2026

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 Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

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Overcoming Resistance to the THZ Series of Covalent Transcriptional CDK Inhibitors

Yang Gao1, Tinghu Zhang2, Hideki Terai3

  • 1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.

Cell Chemical Biology
|December 26, 2017
PubMed

Insights

Cancer cells can resist CDK inhibitors by increasing drug efflux pumps. Researchers developed a new inhibitor, E9, that bypasses these pumps, offering a promising therapeutic strategy for overcoming treatment resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Transcriptional cyclin-dependent kinases (CDKs) are therapeutic targets in cancers with aberrant transcription.
  • Resistance mechanisms to CDK inhibitors can limit their clinical efficacy.
  • Multidrug transporters ABCB1 and ABCG2 are known contributors to drug resistance.

Purpose of the Study:

  • To identify resistance mechanisms to the CDK inhibitor THZ1.
  • To develop a novel CDK inhibitor that overcomes ABC transporter-mediated resistance.
  • To elucidate the mechanism of action and resistance for new CDK inhibitors.

Main Methods:

  • Investigated resistance to THZ1 in neuroblastoma and lung cancer models.
  • Demonstrated upregulation of ABCB1 and ABCG2 as a resistance mechanism.
  • Developed a new CDK inhibitor, E9, designed to evade ABC transporters.
  • Utilized resistance selection to determine the specific target and modification site of E9.

Main Results:

  • Upregulation of ABCB1 and ABCG2 confers resistance to THZ1.
  • The novel CDK inhibitor E9 is not a substrate for ABC transporters.
  • E9 exerts cytotoxic effects via covalent modification of CDK12 at cysteine 1039.
  • Target deconvolution of E9 was achieved through resistance selection.

Conclusions:

  • ABCB1 and ABCG2-mediated drug efflux is a significant resistance mechanism to THZ1.
  • The CDK inhibitor E9 offers a strategy to overcome ABC transporter-mediated resistance.
  • Target deconvolution via resistance selection is a viable method for characterizing novel inhibitors.
Keywords:
covalent transcriptional CDK inhibitordrug resistancepediatric and adult solid tumors

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