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Efficient optimization of pyrazolo[3,4-d]pyrimidines derivatives as c-Src kinase inhibitors in neuroblastoma

Alessio Molinari1, Anna Lucia Fallacara1, Salvatore Di Maria1

  • 1Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy.

Bioorganic & Medicinal Chemistry Letters
|September 29, 2018
PubMed

Insights

Researchers optimized pyrazolo[3,4-d]pyrimidines to create novel c-Src inhibitors. These compounds show nanomolar inhibition, antiproliferative effects on neuroblastoma cells, and favorable ADME properties for potential cancer therapy.

Area of Science:

  • Biochemistry
  • Oncology
  • Medicinal Chemistry

Background:

  • Proto-oncogene c-Src is a tyrosine kinase regulating cellular processes.
  • c-Src hyperactivation is implicated in various cancers, including neuroblastoma (NB).
  • Previous studies identified pyrazolo[3,4-d]pyrimidines as c-Src inhibitors with NB cell activity.

Purpose of the Study:

  • To optimize pyrazolo[3,4-d]pyrimidine derivatives for enhanced c-Src inhibition.
  • To evaluate antiproliferative activity against SH-SY5Y neuroblastoma cells.
  • To assess the ADME profile of the optimized compounds.

Main Methods:

  • Free Energy Perturbation/Monte Carlo calculations guided structural optimization.
  • In vitro assays measured kinase inhibition (Ki values).
  • Cell-based assays assessed antiproliferative effects on SH-SY5Y cells.

Main Results:

  • A new series of pyrazolo[3,4-d]pyrimidine derivatives was identified.
  • Compounds exhibited nanomolar Ki values against c-Src.
  • Significant antiproliferative activity was observed on SH-SY5Y NB cells.
  • The optimized compounds demonstrated a suitable ADME profile.

Conclusions:

  • The optimized pyrazolo[3,4-d]pyrimidines represent promising c-Src inhibitors.
  • These compounds hold potential for neuroblastoma treatment.
  • Further development is warranted based on efficacy and ADME profile.
Keywords:
NeuroblastomaPyrazolo[3,4-d]pyrimidinec-Src

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