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Pyrazolone-based anaplastic lymphoma kinase (ALK) inhibitors: control of selectivity by a benzyloxy group

Rabindranath Tripathy1, Robert J McHugh, Arup K Ghose

  • 1Cephalon, Inc., Worldwide Discovery Research, 145 Brandywine Parkway, West Chester, PA 19380, USA. rtripath@cephalon.com

Bioorganic & Medicinal Chemistry Letters
|November 9, 2011
PubMed

Insights

Researchers identified novel compounds targeting anaplastic lymphoma kinase (ALK), a key driver in certain cancers. Compound 8 demonstrated broad kinome selectivity and good metabolic stability, showing potential for further development.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Biochemistry

Background:

  • Anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase.
  • Oncogenic variants of ALK are implicated in anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and other malignancies.

Purpose of the Study:

  • To identify and optimize novel inhibitors targeting ALK.
  • To investigate structure-activity relationships (SAR) for ALK inhibition.

Main Methods:

  • Screening of a VEGFR2-biased kinase library identified initial ALK cross-reactivity.
  • Structure-activity relationship (SAR) studies focused on modifying indole and heterocyclic segments.
  • Docking studies were performed to understand binding interactions.
  • Cellular potency was assessed in ALK-positive ALCL cells (Karpas-299).

Main Results:

  • A structural modification (ethoxy to benzyloxy) enhanced potency and selectivity for ALK.
  • Thiazole-bearing pyrazolones maintained enzyme potency and inhibited NPM-ALK autophosphorylation.
  • Compound 8 exhibited broad kinome selectivity and good liver microsome stability.
  • Compound 8 showed reasonable intravenous pharmacokinetic (PK) properties in rats but limited oral exposure.

Conclusions:

  • Novel ALK inhibitors were developed through systematic SAR studies.
  • Compound 8 represents a promising lead compound with favorable selectivity and stability profiles.
  • Further optimization is needed to improve oral bioavailability for potential therapeutic applications.

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