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Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor

Steven R Whittaker1, Clare Barlow1, Mathew P Martin2

  • 1Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.

Molecular Oncology
|October 25, 2017
PubMed

Insights

A new drug, CCT068127, effectively inhibits cyclin-dependent kinases (CDK2 and CDK9), showing promise for cancer treatment. This CDK inhibitor demonstrates potent anti-cancer activity and synergizes with BCL2 inhibitors for enhanced therapeutic effects.

Area of Science:

  • Molecular Biology
  • Cancer Therapeutics
  • Pharmacology

Background:

  • Cyclin-dependent kinases (CDKs) are frequently deregulated in cancer, making them critical therapeutic targets.
  • Existing CDK inhibitors like seliciclib provide a foundation for developing more potent and selective agents.
  • Understanding the molecular mechanisms of CDK inhibition is crucial for advancing cancer treatment strategies.

Purpose of the Study:

  • To investigate the molecular and cellular effects of CCT068127, a novel inhibitor targeting CDK2 and CDK9.
  • To evaluate the antiproliferative activity and therapeutic potential of CCT068127 in human cancer cell lines.
  • To explore the synergistic effects of CCT068127 in combination with other targeted cancer therapies.

Main Methods:

  • Enzymatic assays to determine potency and selectivity against purified CDK2 and CDK9.
  • X-ray crystallography to elucidate the binding mechanism of CCT068127 with CDK2.
  • Cell-based assays to assess antiproliferative activity, cell cycle effects, apoptosis, and pathway modulation in colon cancer and melanoma cells.

Main Results:

  • CCT068127 demonstrated enhanced potency and selectivity for CDK2 and CDK9 compared to its precursor, seliciclib.
  • The drug induced cell cycle arrest and apoptosis by inhibiting RB and RNA polymerase II phosphorylation.
  • CCT068127 showed synergistic antiproliferative effects when combined with BCL2 family inhibitors, partly due to MCL1 downregulation.

Conclusions:

  • CCT068127 is a potent CDK2/9 inhibitor with significant antiproliferative activity against human cancer cells.
  • Its mechanism involves disruption of cell cycle progression and induction of apoptosis.
  • The combination of CCT068127 with BCL2 inhibitors presents a promising therapeutic strategy for cancer treatment.
Keywords:
CDKABT263CCT068127MCL1seliciclib

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