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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
Summary
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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