Design, synthesis and evaluation of a fluorescent PI3K inhibitor as a dual-function agent toward Cancer Theranostics

The development of PI3K-targeted therapeutics has advanced significantly, yet molecular tools capable of simultaneous kinase inhibition and real-time visualization of drug distribution remain limited. Herein, we describe the rational design, synthesis, and biological evaluation of a novel fluorescent PI3K inhibitor (compound 1) that incorporates a 4-methylquinazoline pharmacophore conjugated to fluorescein isothiocyanate (FITC) through a piperazine linker. 1 demonstrated potent PI3K enzymatic inhibition and exhibited significant antiproliferative effects against HGC-27 and MCF-7 cancer cell lines. Mechanistic investigations revealed that 1 effectively suppresses DNA synthesis, triggers G0/G1 cell cycle arrest, and disrupts mitochondrial architecture. Fluorescence-based cellular and in vivo imaging studies demonstrated the compound's preferential cytoplasmic localization and tumor-targeting properties. This dual-function inhibitor not only advances PI3K-targeted drug discovery but also provides a valuable tool for real-time monitoring of drug distribution, representing a promising addition to the growing field of cancer theranostics.