The targeting of phosphatidylinositol 3-kinase (PI3K) by selective inhibitors has emerged as a newer therapeutic option to reduce the burden of the cancer. The involvement of PI3K/mTOR in the progression of breast cancer is widely documented, and, as a result, numerous compounds are being assessed in clinical trials. In our previous study, we have discovered novel small molecules targeting breast cancer both in vitro and in vivo in micromolar concentration. Thus, in the present study, we intended to develop novel 1,3,5-triazine-thiozolidine based dual PI3K/mTOR inhibitor against breast cancer.
The compounds were synthesized in excellent yield and subsequently tested for anticancer activity against ER-positive (MCF-7) and ER-negative (MDA-MB-231) human breast cancer cell lines and MCF 12A (normal epithelial breast cell line) using MTT assay. The inhibitory activity against PI3K and mTOR were also estimated. The 3D-crystal structure of both PI3K and mTOR was used for the docking with DDD-251 to explore key structural contacts.
The anticancer activity data revealed that compound DDDL-251 exhibits potent anticancer activity against MCF-7 and MDA-MB-231 cell lines, with the IC50 of 0.34 µM and 0.98 µM, respectively. The results of cell cycle analysis indicated that DDDL-251 causes G1/S cell cycle arrest. It was also shown to attenuate the PI3K and mTOR with IC50 of 4.05 µM and 6.55 µM, respectively. The docking analysis suggests that, DDDL-251 was able to fit into the ATP pocket of catalytic site of both PI3K amd mTOR with the Ki of 5.02 µM and 8.62 µM, respectively. Moreover, the compound was found non-toxic to the MCF 12A cells.
Based upon the potent anti-breast cancer activity, non-toxicity and selective targeting of both PI3K and mTOR, compound DDDL-251 could serve as a lead for future inhibitors.
Clinical trial identification
Legal entity responsible for the study
Sam Higginbottom University of Agriculture, technology and Sciences.
Sam Higginbottom University of Agriculture, Technology and Sciences.
All authors have declared no conflicts of interest.