Design, Synthesis And Anti-tumor Activities Of Abl And Pi3k Dual Target Inhibitor

Protein tyrosine kinases with a variety of cell functions are extremely important materials in signal transduction. Overexpression of protein tyrosine kinases can activate downstream signaling pathways, which could lead to cell transformation, proliferation, anti-apoptosis and promotion of cell survival, eventually tumor occurrence. ABL tyrosine kinase as a target for the molecular design has successfully led to the launch of such drug as Imatinib, Dasatinib, etc, but there has been clinical drug resistance. Studies have shown that compensatory PI3K/AKT/mTOR signaling pathway could regulate Imatinib resistance development. Therefore, molecular design aimed at both ABL and PI3K has emerged as an attractive target in drug R&D nowdays.In this paper, we virtually screened the PubChem and MDDR database aiming at searching ABL and PI3K dual-inhibitors with SVM (Support Vector Machine) as model and the hits were further evaluated by "Lipinski'rule of 5", molecular docking and the synthesis accessibility. Some compounds bearing (S)-3-aminopyrrolidine were ultimately determined to be designed and synthesized.The anti-tumor activity of the synthesized compounds was tested by the MTT method in vitro against HepG-2 (Human Liver Cancer), MCF-7 (Human Breast Cancer) and K562 (Leukemia) cell Lines. The results showed that these compounds could inhibit the three cell lines, in which K562 cell line were selectively inhibited. Kinase assay showed that compounds 5k-5m could inhibit ABL and PI3K(alpha) kinases, as well as block PI3K/AKT signaling pathway; Apoptosis assasy indicated that the potent antiproliferative activity of these compounds is indeed due to their inhibition on both ABL and PI3K kinases.Although the inhibitory effect of the desigend compounds against the each target is not satisfactory, the synergy makes them show good cellular activity and morerover, the dual inhibitors of ABL and PI3K bearing (S)-3-aminopyrrolidine were not reported before. Based on these hit compounds, it is hoped to design dual inhibitors of ABL and PI3K with more novel strutures, more potent activities and more selectivity by which provide possibility to overcome Imatinib resistance.