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Small-molecule activation of the tumor suppressor kinase LKB1 via the pseudokinase STRAD

Lin Song Kretschmer1, Dominique C Mitchell1, Jin Liu2

  • 1Division of Hematology/Oncology, University of California, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.

Cell Chemical Biology
|August 18, 2026
PubMed

Insights

Researchers developed novel compounds that activate the tumor suppressor kinase LKB1 by targeting STRAD. This approach augments tumor-suppressive signaling and reduces cancer cell viability, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeted therapies in oncology typically inhibit oncogenic kinases.
  • Augmenting tumor-suppressive signaling is a potential alternative but faces challenges in designing activators.
  • Inactivation of the tumor suppressor kinase LKB1 correlates with poor prognosis and therapeutic resistance in cancer.

Purpose of the Study:

  • To explore the therapeutic potential of activating LKB1 signaling.
  • To identify and develop novel allosteric activators for LKB1.
  • To investigate the effect of augmented LKB1 function on cancer cell viability.

Main Methods:

  • Focused on the LKB1 signaling complex, which includes MO25 and STRAD.
  • Exploited the nucleotide binding pocket of STRAD, a pseudokinase, for allosteric activation strategy.
  • Developed and tested STRAD-binding compounds for their ability to activate LKB1.

Main Results:

  • Successfully developed compounds that bind to STRAD and activate LKB1 kinase activity.
  • Demonstrated that activated LKB1 augments tumor-suppressive signaling pathways.
  • Observed a reduction in cancer cell viability in response to LKB1 activation.

Conclusions:

  • Targeting STRAD offers a viable strategy for allosteric activation of LKB1.
  • Augmenting LKB1 function through novel compounds can reduce cancer cell viability.
  • This approach holds promise for treating cancers with intact LKB1 genes, especially those resistant to current therapies.
Keywords:
LKB1STRADpseudokinasesmall-molecule activatortumor suppressor kinase

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