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ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

Hetal Patel1, Manikandan Periyasamy1, Georgina P Sava1

  • 1Division of Cancer, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.

Molecular Cancer Therapeutics
|March 17, 2018
PubMed

Insights

A new drug, ICEC0942, selectively inhibits Cyclin-dependent kinase (CDK)7, a key enzyme in transcription. This inhibition shows promise as a new cancer treatment, particularly for ER-positive breast cancer, both alone and with hormone therapies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Cancer cells can be sensitive to transcription inhibition.
  • Cyclin-dependent kinase (CDK)7 is crucial for transcription initiation and regulates transcription factors like estrogen receptor (ER)-α.
  • Targeting transcriptional machinery offers novel cancer treatment strategies.

Purpose of the Study:

  • To introduce and evaluate ICEC0942, a novel, orally bioavailable inhibitor of CDK7.
  • To assess the efficacy of CDK7 inhibition in various cancer types.
  • To explore the potential of ICEC0942 as a single agent or in combination therapy.

Main Methods:

  • Development of a selective CDK7 inhibitor, ICEC0942.
  • In vitro assessment of cancer cell sensitivity to CDK7 inhibition (GI50 values).
  • In vivo studies using breast and colorectal cancer xenografts, including combination therapy with tamoxifen.

Main Results:

  • ICEC0942 selectively inhibits CDK7 with high potency (IC50 = 40 nmol/L) and minimal off-target activity against related kinases.
  • Broad in vitro sensitivity to CDK7 inhibition across various cancer types was observed (GI50 = 0.2–0.3 µmol/L).
  • ICEC0942 demonstrated significant antitumor effects in breast and colorectal cancer xenografts and achieved complete growth arrest in ER-positive tumors when combined with tamoxifen.

Conclusions:

  • CDK7 inhibition represents a promising new therapeutic avenue for cancer, especially ER-positive breast cancer.
  • ICEC0942 is a potential drug candidate for monotherapy or combination treatment with hormone therapies.
  • ICEC0942 may also benefit cancers dependent on transcription factors, such as acute leukemia and small-cell lung cancer.

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