Small molecule-based drug design of anticancer agents that target protein kinase B/AKT, Bcl-xL and DNA methyltransferases for the treatment of prostate cancer.

摘要

Prostate cancer is the most common form of cancer in men and the second leading cause of cancer-related deaths in the United States. So far, several mechanisms have been identified by which androgen-independent prostate cancer can develop, including constitutively active AKT pathway, overexpression of Bcl-xL and hypermethylation of tumor suppressor and caretaker genes, such as RASSF1A and GSTP1. In this dissertation research, we have developed three classes of anticancer agents that target the AKT signaling pathway, Bcl-xL, and DNA methyltransferases based on small molecules as our molecular templates.; In terms of targeting the AKT pathway, we examined the antiproliferative effect of our lead compound doxazosin, our pharmacological study revealed that doxazosin's apoptotic effect was mediated, in part, through the down-regulation of phospho-AKT. Therefore, a systematic modification of doxazosin was carried out yielding the optimal compounds 33 and 44 which exhibited an order of magnitude improvement in antiproliferative potency.; Development of the Bcl-xL inhibitor arose from our attempt to develop non-nucleoside DNA hypomethylating agents based on procainamide and procaine as molecular templates. However, the antiproliferative effects of these procainamide derivatives in PC-3 cells could not be attributed to the alteration of DNA methylation status. A search for a molecular target of these agents attributed their antiproliferative effect in PC-3 cells to the inhibition of Bcl-xL function. Among these derivatives, compound 27 exhibited the greatest inhibitory effect against Bcl-xL activity. Exposure of PC-3 cells to 27 resulted in the release of cytochrome c from mitochondria, followed by the activation of caspase-9 and PARP cleavage.; To continue our research on the development of non-nucleoside DNA hypomethylating agents, (-)-epicatechin gallate (ECG) was selected as our molecular template based on the literature describing its ability to inhibit DNA methyltransferase (DNMT) activity. Screening of some candidates by methylation-specific PCR (MSP) in three cancer cell lines indicated that RASSF1A gene could be consistently demethylated by compound 6A.; Altogether, through this dissertation research, we have successfully developed three classes of anticancer agents that modulate different molecular targets. These findings suggest that small molecule-based drug design can be a powerful tool to develop more structurally diversified anticancer agents.