Discovery of a novel photoswitchable PI3K inhibitor toward optically-controlled anticancer activity

Area of Science:

• Medicinal Chemistry
• Photopharmacology
• Oncology

Background:

• Light-activated therapeutics offer precise control over drug activity.
• The phosphoinositide 3-kinase (PI3K) pathway is a critical target in cancer therapy.
• Developing controllable inhibitors for the PI3K pathway is an active area of research.

Purpose of the Study:

• To design and synthesize a novel photoswitchable inhibitor targeting the PI3K pathway.
• To investigate the photochemical and photobiological properties of the synthesized compound.
• To evaluate the compound's efficacy in preclinical cancer models.

Main Methods:

• Synthesis of an azobenzene-containing PI3K inhibitor.
• Characterization of photochemical properties using UV-Vis spectroscopy, LC-MS, and NMR.
• In vitro assessment of anticancer activity, including PI3K pathway inhibition, cell migration, and colony formation assays.
• In vivo evaluation using a zebrafish xenograft tumor model.

Main Results:

• The synthesized azo-PI3K inhibitor efficiently switches between trans and cis isomers upon light irradiation.
• The trans and cis isomers exhibit differential anticancer activity, affecting PI3K pathway inhibition, cell migration, and colony formation.
• The compound's activity can be switched at the cellular level with light.
• Both isomers demonstrated significant tumor growth inhibition in a zebrafish xenograft model.

Conclusions:

• A novel photoswitchable azo-PI3K inhibitor has been successfully developed.
• The inhibitor demonstrates light-controllable anticancer activity at cellular and in vivo levels.
• This compound serves as a valuable tool for studying the PI3K pathway and developing optically-controlled cancer therapies.