The Identification of Potent, Selective, and Brain Penetrant PI5P4Kγ Inhibitors as In Vivo-Ready Tool Molecules

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Pharmacology

Background:

• Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are crucial regulators of cell signaling pathways.
• Dysregulation of PI5P4Ks is implicated in cancer, neurodegeneration, and immunological disorders, making them key therapeutic targets.
• Existing PI5P4K tool molecules lack sufficient potency or isoform selectivity, hindering biological research and drug development.

Purpose of the Study:

• To identify and optimize novel, potent, and isoform-selective inhibitors of PI5P4Kγ.
• To provide valuable tool compounds for investigating PI5P4Kγ function in disease contexts.
• To facilitate the development of new therapeutic strategies targeting PI5P4K-mediated signaling.

Main Methods:

• Utilized virtual screening to identify initial hit compounds.
• Employed medicinal chemistry optimization to enhance potency and selectivity of identified chemotypes.
• Conducted in vivo pharmacokinetic studies and X-ray crystallography for structural insights.
• Assessed selectivity against a broad panel of kinases (>150) and a Cerep safety panel.

Main Results:

• A series of thienylpyrimidines were identified as PI5P4Kγ-selective inhibitors through virtual screening.
• Medicinal chemistry efforts successfully optimized these compounds, yielding potent and selective tool molecules.
• Exemplar tool molecules demonstrated favorable in vivo pharmacokinetic properties.
• The X-ray structure of ARUK2001607 (15) in complex with PI5P4Kγ provided structural basis for inhibition.
• Compounds exhibited high selectivity against a wide range of kinases and a Cerep safety panel.

Conclusions:

• The developed thienylpyrimidine series represents a significant advancement in PI5P4Kγ inhibitor discovery.
• These potent and selective tool molecules are suitable for further biological investigation and drug discovery efforts.
• The findings pave the way for exploring PI5P4Kγ as a therapeutic target in various diseases.