Related Experiment Video

Updated: Jun 13, 2025

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

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Discovery and Characterization of Potent, Selective, and Orally Bioavailable 7-Azaindazole AXL Receptor Tyrosine

Corinne N Foley1, Shiwei Qu1, Srinivas Reddy Paladugu1

  • 1Arcus Biosciences, Inc., Hayward, California 94545, United States.

Journal of Medicinal Chemistry
|May 23, 2025
PubMed

Insights

Researchers developed novel AXL inhibitors to combat cancer drug resistance. A lead compound, AB801, shows promise for clinical development, offering a new therapeutic strategy for AXL-driven cancers.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Pharmacology

Background:

  • High expression of receptor tyrosine kinase AXL correlates with poor prognosis and treatment resistance in various cancers.
  • Targeting AXL is a potential strategy to overcome resistance to standard cancer therapies.
  • The therapeutic window and efficacy of existing AXL inhibitors in blocking tumor signaling remain unclear.

Purpose of the Study:

  • To design and optimize novel 7-azainazole-based AXL inhibitors.
  • To identify a tool compound for in vivo validation of AXL inhibition.
  • To discover a clinical development candidate with improved properties for treating AXL-driven cancers.

Main Methods:

  • Structure-activity relationship (SAR) studies guided the optimization of 7-azainazole derivatives.
  • In vivo studies were conducted using a tool compound to assess anti-tumor efficacy.
  • Lead optimization focused on achieving desired potency, selectivity, bioavailability, and safety profiles.

Main Results:

  • A novel series of 7-azainazole AXL inhibitors was successfully developed.
  • An optimized tool compound demonstrated significant tumor volume reduction in combination therapy.
  • Lead compound 68 exhibited favorable potency, kinome selectivity, oral bioavailability, and safety.
  • Clinical development candidate AB801 was identified through further optimization.

Conclusions:

  • The SAR-driven optimization yielded potent and selective AXL inhibitors.
  • The developed compounds, including AB801, represent promising therapeutic agents for AXL-related cancers.
  • This research provides a foundation for advancing AXL-targeted therapies in clinical settings.

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