Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues

Targeted antitumour therapies have transformed the treatment landscape for various tumour types, with phosphatidylinositol-3 kinase (PI3K) emerging as a key validated target. Among the PI3K inhibitors developed for cancer treatment is gedatolisib (4), which served as a prototype for designing a new series of simplified analogues (5a-f) through targeted molecular modifications. These analogues were synthesized, and their cytotoxic activity was evaluated using phenotypic models of both solid and nonadherent tumour cell lines. Notably, compound 5f (LASSBio-2252) emerged as the most promising candidate, exhibiting favorable aqueous solubility (42.38 μM at pH 7.4; 39.33 μM at pH 5.8), a balanced partition coefficient (cLogP = 2.96), potent cytotoxic activity against human leukemia cell lines (CCRF-CEM, K562, and MOLT-4), and excellent metabolic stability in rat liver microsomes (t1/2 = 462 min; Clapp = 0.058 mL/min/g). Flow cytometry analysis confirmed that 5f exerts its cytotoxic effects through modulation of the PI3K pathway, comparable to gedatolisib.