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Author Spotlight: Identifying Compensatory Pathways in Malaria Parasites Containing Hypomorphic Allele of Essential Protein Kinases

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Chemical evolution for taming the 'pathogenic kinase' PAK1

Hiroshi Maruta1, Atsushi Kittaka2

  • 1PAK Research Center, Melbourne, Australia.

Drug Discovery Today
|April 30, 2020
PubMed

Insights

p21-activated kinases (PAKs) are crucial in diseases like cancer and infections. New PAK1 blockers, developed through chemical evolution, show over 500x boosted activity for potential clinical use.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • The first mammalian p21-activated kinases (PAKs) were cloned 25 years ago, leading to the first international PAK symposium.
  • Six distinct PAKs exist in mammals, with PAK1 identified as a major 'pathogenic kinase' involved in various diseases.

Purpose of the Study:

  • To highlight the significance of PAK1 in diseases including cancers, aging, and infectious/inflammatory conditions.
  • To discuss recent advancements in developing potent PAK1 blockers for clinical applications.

Main Methods:

  • Review of research on PAK1's role in pathogenesis.
  • Description of 'chemical evolution' strategies used to develop novel PAK1 blockers from existing compounds like triptolide, vitamin D3, and ketorolac.

Main Results:

  • Abnormal activation of PAK1 is linked to numerous diseases, including cancers, aging, and pandemic coronaviral infections.
  • Development of highly cell-permeable and water-soluble PAK1 blockers with over 500-fold increased pharmacological activity.

Conclusions:

  • PAK1 is a critical therapeutic target for a range of diseases.
  • Advanced PAK1 blockers demonstrate significant potential for clinical translation in treating various pathological conditions.

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