Design, synthesis and bioevaluation of PI3Kα-selective inhibitors as potential colorectal cancer drugs

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is frequently dysregulated in human cancers.
• Targeting PI3Kα with isoform-selective inhibitors is a promising therapeutic strategy for cancer treatment.

Purpose of the Study:

• To design and synthesize novel substituted benzoxazole derivatives as PI3Kα inhibitors.
• To identify an optimal compound with improved potency, selectivity, and pharmacokinetic properties compared to the clinical candidate TAK-117.

Main Methods:

• Synthesis of three series of substituted benzoxazole derivatives.
• Structure-activity relationship (SAR) studies to optimize compound efficacy.
• In vitro assays to evaluate PI3Kα inhibitory activity, isoform selectivity, and antiproliferative effects.
• Pharmacokinetic studies to assess in vivo performance.

Main Results:

• Compound 18a, featuring a quinoxaline scaffold, was identified as the optimal derivative.
• 18a demonstrated a 4.4-fold increase in PI3Kα inhibitory potency (IC50: 2.5 nM) and superior isoform selectivity compared to TAK-117.
• 18a exhibited a 1.5-fold more potent antiproliferative effect against HCT-116 cells and better selectivity over normal cells.
• Pharmacokinetic analysis revealed higher plasma exposure and maximum concentration for 18a.

Conclusions:

• Novel benzoxazole derivatives, particularly compound 18a, represent promising PI3Kα inhibitors for cancer therapy.
• Compound 18a displays enhanced potency, selectivity, and favorable pharmacokinetic profiles, warranting further investigation.
• The developed compounds hold potential for the treatment of cancers driven by PI3K pathway dysregulation.