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Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development

Jeffrey M Axten1, Stuart P Romeril1, Arthur Shu1

  • 1Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.

ACS Medicinal Chemistry Letters
|June 6, 2014
PubMed

Insights

Researchers optimized a protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) inhibitor, GSK2656157, to improve drug properties. This new compound shows promise for further preclinical development as a cancer therapeutic.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a key regulator of cellular stress.
  • PERK signaling is implicated in various diseases, including cancer.
  • Previous discovery of GSK2606414, a selective PERK inhibitor, showed potential in preclinical models.

Purpose of the Study:

  • To optimize the physicochemical and pharmacokinetic properties of a PERK inhibitor.
  • To discover novel PERK inhibitors with improved drug-like characteristics.
  • To identify a candidate for further preclinical development.

Main Methods:

  • Medicinal chemistry optimization strategy focused on reducing lipophilicity.
  • Structure-activity relationship studies to guide inhibitor design.
  • Evaluation of cellular activity and in vivo efficacy of optimized compounds.

Main Results:

  • Discovery of GSK2656157, a novel PERK inhibitor with reduced lipophilicity.
  • GSK2656157 demonstrated improved physical properties and pharmacokinetic profile compared to previous analogs.
  • The compound exhibited potent inhibition of PERK signaling in cellular assays.

Conclusions:

  • Medicinal chemistry efforts successfully yielded an optimized PERK inhibitor, GSK2656157.
  • The improved properties of GSK2656157 support its advancement to preclinical development.
  • This optimized inhibitor represents a promising therapeutic candidate for diseases involving PERK signaling.
Keywords:
PERKUPRfluorine interactionkinaselead optimizationstructure−activity relationship

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