Development of new kinase inhibitors as targeted cancer therapeutics

Abstract

This thesis is about development of new kinase inhibitors as targeted cancer therapeutics. The research has two main purposes; one is producing new anticancer agent able to overcome resistance, a major problem faced in present clinical treatment and the other is investigating cancer involved bio-mechanism which has not been established clearly from a biological point.

Part 1. Discovery of New Benzothiazole-based Derivatives as Potent Breakpoint Cluster Region-Abelson Kinase and T315I Mutant Inhibitors The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (BCR-ABL) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant BCR-ABL kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. In addition, the introduction of water-solubilizing groups at the terminal ethyl group resulted in enhanced physicochemical properties and potency in cellular inhibition. Several compounds inhibited the kinase activity of both wild-type BCR-ABL and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative effects on Ba/F3 cell lines transformed with either wild-type or T315I mutant BCR-ABL.

Keywords: break-point cluster region-Abelson tyrosine kinase, chronic myeloid leukemia, benzothaizole, T315I mutation

Part 2. Study of Cross Talk between Trk and PI3K with Development of 7-Azaindole-based Inhibitors Having Anticancer and Antiangiogenic Activity As Phosphatidylinositol-3-kinase (PI3K) is a downstream effector of Tropomyosin-related kinase (Trk), two kinases are closely related in cell signal transduction. Each kinase is an important therapeutic target in cancer...