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Unfolded Protein Response in Cancer: IRE1α Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell

Paul E Harrington1, Kaustav Biswas1, David Malwitz1

  • 1Departments of Medicinal Chemistry, Molecular Structure, and Oncology, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 93012, United States.

ACS Medicinal Chemistry Letters
|January 16, 2015
PubMed

Insights

Researchers developed inhibitors targeting the inositol requiring enzyme 1-alpha (IRE1α) kinase/endonuclease. However, these potent IRE1α inhibitors did not affect tumor cell viability, suggesting UPR inhibition is not an effective anticancer strategy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • The unfolded protein response (UPR) is triggered by endoplasmic reticulum stress.
  • Inositol requiring enzyme 1-alpha (IRE1α) is a key sensor in the UPR pathway.
  • IRE1α has been explored as a potential anticancer target due to its role in cell survival.

Purpose of the Study:

  • To identify and characterize novel allosteric inhibitors of IRE1α endonuclease activity.
  • To evaluate the efficacy of IRE1α inhibition in cancer cell viability.
  • To assess the therapeutic potential of targeting IRE1α in cancer treatment.

Main Methods:

  • Structure-activity relationship (SAR) studies were conducted to optimize IRE1α inhibitors.
  • Inhibitor potency was assessed against recombinant and cellular IRE1α.
  • X-ray crystallography was used to determine the structure of an inhibitor bound to IRE1α.
  • High-throughput screening of over 300 native tumor cell lines was performed.

Main Results:

  • Potent allosteric inhibitors (compounds 16 and 18) targeting IRE1α were identified.
  • Inhibitors demonstrated selectivity in kinase screens and potent activity against IRE1α.
  • The first X-ray crystal structure of an IRE1α kinase inhibitor complex was obtained.
  • No significant effect on the viability of tested tumor cell lines was observed with selective IRE1α inhibitors.

Conclusions:

  • IRE1α activity is not essential for the in vitro viability of most tumor cell lines.
  • Targeting IRE1α and its survival functions within the UPR may not be a viable strategy for blocking tumorigenesis.
  • Further research is needed to explore alternative therapeutic targets for cancer treatment.
Keywords:
IRE1αUnfolded protein responseinhibitorkinase

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