Optimization of Orally Bioavailable PI3Kδ Inhibitors and Identification of Vps34 as a Key Selectivity Target

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Phosphoinositide 3-kinase delta (PI3Kδ) is a key target in various diseases.
• Early inhibitors based on a dihydroisobenzofuran core showed promise but lacked selectivity and had toxicity issues.

Purpose of the Study:

• To optimize PI3Kδ inhibitors for improved potency, selectivity, and pharmacokinetic properties.
• To address the off-target activity and toxicity observed in initial lead compounds.

Main Methods:

• Structure-based drug design was employed to enhance selectivity.
• Lead optimization focused on improving oral pharmacokinetic profiles.
• In vitro and in vivo studies were conducted to assess potency, selectivity, and toxicology.

Main Results:

• Compound 19, a potent PI3Kδ inhibitor, exhibited cross-reactivity with Vps34 (PI3K Class III) and poor tolerability in rats.
• Structure-based design improved selectivity for PI3Kδ over Vps34.
• Compound 41 demonstrated improved pharmacokinetic properties and better toxicological outcomes compared to compound 19 at similar exposure levels.

Conclusions:

• Optimization efforts successfully yielded PI3Kδ inhibitors with improved selectivity and safety profiles.
• Compound 41 represents a promising candidate for further development as a PI3Kδ-targeted therapeutic.