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Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase

Marialuisa Moccia1, Qingsong Liu2, Teresa Guida1

  • 1Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", Naples, Italy; Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy.

Plos One
|June 6, 2015
PubMed

Insights

Three novel type II RET tyrosine kinase inhibitors (TKIs) show potent activity against oncogenic RET mutants in human cancers. These inhibitors, effective at nanomolar concentrations, target resistant mutations and offer a promising new therapeutic lead for RET-driven malignancies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Oncogenic mutations in the RET receptor tyrosine kinase drive several human cancers.
  • Developing targeted therapies for RET-driven malignancies remains a critical unmet need.

Purpose of the Study:

  • To identify and characterize novel type II RET tyrosine kinase inhibitors (TKIs).
  • To evaluate the efficacy of these inhibitors against various oncogenic RET mutants, including drug-resistant forms.

Main Methods:

  • Synthesis and characterization of three novel type II RET TKIs: ALW-II-41-27, XMD15-44, and HG-6-63-01.
  • In vitro assays to assess inhibition of RET kinase activity, signaling, and proliferation in cancer cell lines and transformed fibroblasts.
  • Evaluation of inhibitor efficacy against wild-type and mutant RET forms, including the gatekeeper V804M mutation.

Main Results:

  • ALW-II-41-27, XMD15-44, and HG-6-63-01 demonstrated potent inhibition of oncogenic RET mutants at nanomolar concentrations.
  • These compounds stabilize the 'DFG-out' inactive conformation of RET, blocking downstream signaling and cellular proliferation.
  • Effective inhibition was observed in RET-driven thyroid cancer cell lines and against the resistant V804M mutant.

Conclusions:

  • A novel type II TKI scaffold, exemplified by ALW-II-41-27, XMD15-44, and HG-6-63-01, has been identified.
  • These inhibitors represent promising lead compounds for developing new therapeutic agents for RET-dependent cancers.
  • The identified scaffold shows potential for overcoming resistance to existing RET inhibitors.

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