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Pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives as new multi-targeted inhibitors of Aurora A/B and KDR

Qiumeng Zhang1, Qianqian Shen2, Lixin Gao3

  • 1Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China; National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.

European Journal of Medicinal Chemistry
|September 22, 2018
PubMed

Insights

New pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives show potent inhibition of Aurora A/B and KDR kinases, crucial for cancer growth. Compound 17g, a promising multi-targeted lead, warrants further investigation.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Pharmacology

Background:

  • Aurora A, Aurora B, and Kinase Insert Domain-containing Receptor (KDR) are key targets in sustained cancer growth.
  • Developing novel inhibitors against these targets is crucial for effective cancer therapy.

Purpose of the Study:

  • To design and synthesize novel pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives.
  • To evaluate the enzymatic activities of these derivatives against Aurora A/B and KDR.
  • To assess the anti-proliferative and pharmacokinetic properties of promising compounds.

Main Methods:

  • Synthesis of eighteen pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives.
  • In vitro enzymatic assays to determine IC50 values against Aurora A/B and KDR.
  • Cell-based assays for anti-proliferative activity, cell cycle arrest, and apoptosis.
  • In vivo studies to evaluate tumor inhibition and pharmacokinetic profiles.

Main Results:

  • Most synthesized compounds demonstrated significant Aurora A/B and KDR inhibitory activities.
  • Compound 17g exhibited potent inhibition with IC50 values of 46.2 nM (Aurora A), 37.6 nM (Aurora B), and 21.6 nM (KDR).
  • Compound 17g showed moderate anti-proliferative effects, induced G2/M cell cycle arrest and apoptosis, possessed good pharmacokinetics (63.8% bioavailability), and inhibited tumor growth in vivo.

Conclusions:

  • The pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine scaffold is a promising foundation for developing multi-targeted inhibitors of Aurora A/B and KDR.
  • Compound 17g is a potential lead compound for further preclinical development due to its potent multi-targeted activity and favorable biological profile.
Keywords:
AnticancerAurora AAurora BHeterocyclicKDRMulti-targeted

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