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Un-LOK-ing a New Approach for Conformational Selective Targeting of STK10 (LOK)

Martina Dettenhöfer1,2, Laura Nadine Tandara1,2, Jennifer Alisa Amrhein1,2

  • 1Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.

ACS Medicinal Chemistry Letters
|November 19, 2025
PubMed

Insights

Researchers optimized a macrocyclic scaffold to develop a urea-based inhibitor targeting serine/threonine kinase 10 (STK10). This new compound demonstrates potent and selective inhibition of STK10, offering a promising therapeutic strategy.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Serine/threonine kinase 10 (STK10), also known as LOK, regulates critical cellular functions including cell cycle and lymphocyte migration.
  • Dysregulated STK10 activity is implicated in diseases characterized by abnormal cell migration and division, identifying it as a therapeutic target.

Purpose of the Study:

  • To optimize a macrocyclic pyrazolo-[1,5-a]-pyrimidine scaffold for developing novel STK10 inhibitors.
  • To identify potent and selective inhibitors targeting the unique back-pocket of STK10.

Main Methods:

  • Late-stage optimization of a macrocyclic scaffold.
  • Co-crystal structure analysis to elucidate binding mode.
  • Biophysical assays, cellular activity assays, and kinome selectivity profiling.

Main Results:

  • A urea-based lead series targeting the STK10 back-pocket was developed.
  • Compound 23 adopted a unique binding mode, extending deep into the STK10 back-pocket.
  • Compound 23 demonstrated potent on-target activity, nanomolar cellular potency, and high selectivity against the kinome and SLK.

Conclusions:

  • Targeting the unique, extended back-pocket of STK10 offers a strategy for developing highly selective STK10 inhibitors.
  • Compound 23 represents a promising lead for further therapeutic development for STK10-related diseases.
Keywords:
conformational changeinhibitor binding modekinase inhibitor selectivitymacrocyclic inhibitorrational inhibitor designserine/threonine kinase 10

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