Akt pathway presents an exciting new target for molecular therapeutics, as it functions as a cardinal nodal point for transducing extracellular (growth factor and insulin) and intracellular (receptor tyrosine kinases, Ras and Src) oncogenic signals. In addition, alterations of the Akt pathway have been detected in a number of human malignancies. Ectopic expression of Akt, especially constitutively activated Akt, is sufficient to induce oncogenic transformation of cells and tumor formation in transgenic mice. Blockage of Akt signaling results in apoptosis and growth inhibition of tumor cells with elevated Akt. The observed dependence of certain tumors on Akt signaling for survival and growth has wide implications for cancer therapy, including breast and liver cancer.
Based on our preliminary studies fundamental to the preparation of this proposal, different chemotypes from in-house combinatorial library were tested against liver and breast cancer cell lines, and a lead compound (EB38) was discovered having potent antiproliferative activity for both cell lines. Our lead compound showed potent cytotoxicity against liver (Huh7 and Mahlavu) and breast (MCF7 and MCF12a) cell lines with IC50 values of <0.1, <0.1, 3.4 and 5.8 μM, respectively. It was further demonstrated that the EB38 caused apoptosis based on the cell cycle arrest at SubG1/G1 phase, inhibition of Akt protein phosphorylation and also by causing increased amounts of cleaved PARP in Mahlavu cell lines. In parallel to the in vitro results, in vivo efficacy of EB38 was demonstrated by its inhibition of tumor volume (50%) in xenografts established with Mahlavu cell lines.
Within the context of these results, lead compound optimization and in vitro/in vivo preclinical studies will be carried out with the aim of developing and patenting novel drug candidates targeting Akt pathway. The main goal of the project is therefore to obtain candidate compounds with optimized drug-like properties (pharmacokinetics), which will be active in in vivo athymic nude mice xenograft tumor models.
Therefore in compliance with the program call, final goal of this project will be met, which is to develop new drug candidates with both optimized drug-like properties and with validated therapeutic target, for treatment and survival rate of breast and liver cancers.