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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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Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: synthesis, X-ray crystal

Hao Shao1, Shenhua Shi, Shiliang Huang

  • 1School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.

Journal of Medicinal Chemistry
|January 11, 2013
PubMed

Insights

Targeting cyclin-dependent kinase 9 (CDK9) with novel anilinopyrimidine derivatives re-establishes cancer cell apoptosis. Compound 12u shows high selectivity and potent anti-cancer activity, particularly against chronic lymphocytic leukemia.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Oncology

Background:

  • Cancer cells evade apoptosis through elevated antiapoptotic proteins.
  • Cyclin-dependent kinase 9 (CDK9) inhibition can restore programmed cell death in cancer.

Purpose of the Study:

  • To design and synthesize novel 4-thiazol-2-anilinopyrimidine derivatives.
  • To evaluate the potency and selectivity of these derivatives against CDK9.
  • To investigate their anticancer activity and binding modes.

Main Methods:

  • Synthesis of anilinopyrimidine derivatives with modifications at C5 or C4 positions.
  • Enzyme inhibition assays to determine IC(50) values and selectivity (e.g., CDK9 vs. CDK2).
  • X-ray crystallography to elucidate binding interactions of compound 12u with CDK9 and CDK2.

Main Results:

  • Compound 12u demonstrated potent CDK9 inhibition (IC(50) = 7 nM) with high selectivity (>80-fold) over CDK2.
  • X-ray structures revealed specific binding modes of 12u to CDK9 and CDK2.
  • 12u exhibited significant anticancer activity against primary chronic lymphocytic leukemia cells, with a notable therapeutic window over normal B- and T-cells.

Conclusions:

  • Novel anilinopyrimidine derivatives, particularly 12u, are effective CDK9 inhibitors.
  • 12u displays selective inhibition and potent anticancer effects, supporting its therapeutic potential.
  • Structural insights aid in understanding structure-activity relationships for rational drug design.

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