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Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1/2)

Apirat Chaikuad1,2, Sebastian E Koschade3,4, Alexandra Stolz2,5

  • 1Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt, Germany knapp@pharmchem.uni-frankfurt.de chaikuad@pharmchem.uni-frankfurt.de.

The Biochemical Journal
|February 21, 2019
PubMed

Insights

Researchers explored ULK2 kinase structure and identified dual ULK1/2 inhibitors for cancer therapy. Off-target effects on Aurora A were noted, impacting autophagy studies and highlighting the need for selective inhibitors.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Autophagy is crucial for cellular balance, but its dysregulation is linked to diseases, including cancer.
  • Inhibiting ULK1 (Unc-51-like autophagy activating kinase 1) is a potential cancer therapy strategy, but ULK2 (Unc-51-like autophagy activating kinase 2) remains less understood.

Purpose of the Study:

  • To determine the crystal structure of ULK2 in complex with inhibitors.
  • To identify potent dual ULK1/2 inhibitors and assess their selectivity.
  • To investigate off-target effects of ULK1 inhibitors.

Main Methods:

  • X-ray crystallography was used to obtain the ULK2-inhibitor complex structure.
  • A focused kinase library was screened for ULK1/2 inhibitors.
  • Off-target analysis identified Aurora A as a target of ULK1 inhibitors.
  • Autophagic flux assays were performed to evaluate cellular effects.

Main Results:

  • The ULK2 crystal structure revealed a dimeric assembly, suggesting a role in kinase activation.
  • Several potent ULK1/2 inhibitors were identified with conserved binding.
  • Aurora A was identified as a significant off-target of ULK1 inhibitors, inducing autophagy.
  • Off-target activity complicates the interpretation of cellular autophagy data.

Conclusions:

  • Structural insights into ULK2 provide a basis for developing dual ULK1/2 inhibitors.
  • Current ULK1 inhibitors have off-target effects on Aurora A, impacting autophagy research.
  • Development of selective ULK1/2 inhibitors is crucial for effective autophagy-targeted therapies.
Keywords:
ULK1ULK2autophagycrystallographykinase inhibitorprotein kinase

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