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Discovery of amido-benzisoxazoles as potent c-Kit inhibitors

Roxanne K Kunz1, Shannon Rumfelt, Ning Chen

  • 1Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. kunz@amgen.com

Bioorganic & Medicinal Chemistry Letters
|August 30, 2008
PubMed

Insights

Researchers developed novel c-Kit inhibitors for treating cancers and mast cell diseases. These inhibitors target c-Kit signaling, offering potential therapeutic advantages with fewer side effects.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • The receptor tyrosine kinase c-Kit plays a crucial role in various human diseases, including cancers and mast cell disorders.
  • Current treatments for c-Kit-associated diseases often involve multi-kinase inhibitors, which have shown efficacy in gastrointestinal stromal tumors and mastocytosis.
  • Targeted inhibition of c-Kit offers potential for improved therapeutic outcomes and reduced off-target effects, particularly for non-oncology applications.

Purpose of the Study:

  • To describe a new structural class of c-Kit inhibitors.
  • To evaluate the in vitro potency and kinase selectivity of these novel inhibitors.
  • To elucidate the binding mode of the new c-Kit inhibitors.

Main Methods:

  • Synthesis and characterization of a novel class of c-Kit inhibitors.
  • In vitro biochemical assays to determine c-Kit inhibitory potency.
  • Kinase panel screening to assess selectivity against other kinases.
  • Co-crystallography or molecular modeling to determine the binding mode.

Main Results:

  • Identification of a new structural class of potent c-Kit inhibitors.
  • Demonstration of high selectivity for c-Kit over a broad range of other kinases.
  • Elucidation of the specific binding interactions within the c-Kit kinase domain.

Conclusions:

  • The novel c-Kit inhibitors represent a promising new therapeutic strategy.
  • Targeted inhibition of c-Kit may offer advantages over current multi-kinase inhibitors.
  • Further investigation into these inhibitors is warranted for potential clinical applications.

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