Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues

Abstract

Targeted antitumour therapy has revolutionized the treatment of several types of tumours. Among the validated targets, phosphatidylinositol-3 kinase (PI3K) deserves to be highlighted. Several PI3K inhibitors have been developed for the treatment of cancer, including gedatolisib (4). This inhibitor was elected as a prototype and molecular modifications were planned to design a new series of simplified gedatolisib analogues (5a-f). The analogues were synthesised, and the comparative cytotoxic activity profile was studied in phenotypic models employing solid and nonadherent tumour cell lines. Compound 5f (LASSBio-2252) stood out as the most promising of the series, showing good aqueous solubility (42.38 μM (pH = 7.4); 39.33 μM (pH = 5.8)), good partition coefficient (cLogP = 2.96), cytotoxic activity on human leukemia cell lines (CCRF-CEM, K562 and MOLT-4) and an excellent metabolic stability profile in rat liver microsomes (t1/2 = 462 min; Clapp = 0.058 mL/min/g). The ability of 5f to exert its cytotoxic effect through modulation of the PI3K pathway was demonstrated by flow cytometry analysis in a comparative manner to gedatolisib.

Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile

“…Considering the cell viability studies in the MTT of 72 h, gedatolisib displayed average cytotoxic concentration (CC 50 ) values of 0.86 µM, 70 nM, 90 nM and 60 nM to PC-3, MOLT-4, CCRF-CEM and MCF-7, respectively. These results are similar to the values of 0.54 µM, 20 nM, 30 nM e 70 nM, respectively, previously described by Costa et al [ 12 ] in regard to the performance of gedatolisib against the same tumour cell lines ( Table 1 ). It is worth noting that our work is the first to describe the cytotoxic effect of gedatolisib in 24 h and 48 h MTT assays on PC-3 and MCF-7 tumour cell lines.…”

Method development and validation for the estimation of gedatolisib in mouse plasma by tandem mass spectrometry and its application to pharmacokinetics studies

“…This new analog has great aqueous solubility and high metabolic stability in rat liver microsomes. Taken together, LASSBio‐2252 (5f) can be considered a new lead candidate, whose structural optimization is required to increase its cytotoxic potency (Costa et al, 2023).…”