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Controlled exploration of structural databases: the case of farnesyl transferase inhibitors

A Tizot1, G C Tucker, A Pierré

  • 1Chemistry Research Division A, SERVIER, 11 rue des Moulineaux, 92150 Suresnes, France. solo.goldstein@fr.netgrs.com.

Medicinal Chemistry (Shariqah (United Arab Emirates))
|May 16, 2009
PubMed

Insights

Farnesyl Transferase Inhibitors (FTI) show promise in cancer treatment by blocking key enzymes. A novel quinazoline-2,4-dione derivative demonstrated potent inhibition of Farnesyl Transferase (FT) and significant anti-cancer activity.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Biochemistry

Background:

  • Farnesyl Transferase Inhibitors (FTI) represent a promising class of anticancer agents.
  • The enzyme Farnesyl Transferase (FT) is crucial for cancer progression, catalyzing protein prenylation, including that of oncogenic Ras proteins.
  • FT activity is a validated target for cancer therapy.

Purpose of the Study:

  • To discover and develop novel Farnesyl Transferase Inhibitors (FTI).
  • To synthesize and characterize quinazoline-2,4-dione analogs with improved Farnesyl Transferase inhibitory properties.
  • To evaluate the in vitro and in vivo efficacy and selectivity of lead compounds.

Main Methods:

  • Database exploration for structural diversity and similarity.
  • Systematic structural modulation of a lead quinazoline-2,4-dione compound.
  • In vitro enzyme inhibition assays to determine IC(50) values for Farnesyl Transferase.
  • Cellular assays using oncogenic H-Ras-transfected cell lines (Ras #1) and parental cell lines (RAT2).
  • In vivo studies to assess anti-tumor activity.

Main Results:

  • A novel quinazoline-2,4-dione derivative was identified with weak FT inhibitory properties.
  • Structural optimization led to compound 21b, exhibiting potent FT inhibition (IC(50) = 19 nM).
  • Compound 21b demonstrated excellent cellular activity against Ras #1 cells and high selectivity (>2000-fold) over parental RAT2 cells.
  • Encouraging in vivo anti-cancer activity was observed for compound 21b.

Conclusions:

  • Novel quinazoline-2,4-dione derivatives are effective Farnesyl Transferase Inhibitors.
  • Compound 21b represents a highly potent and selective FTI with promising therapeutic potential.
  • The structure-activity relationships provide a basis for further development of FTI-based cancer therapies.

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