Development of Targeted Cancer Agents Using a Naturally Occurring Scaffold and Knowledge-Based Design

To date, targeted cancer drugs have been considered as a trend in cancer treatments for obtaining a therapeutic effect with less toxicity compared with traditional chemotherapy. Histone deacetylases (HDACs) play a role in reversible acetylation of histones, transcription factors, and other proteins, which are associated with chromatin remolding and regulation of gene expression. Deacetylation of some non-histone proteins such as tubulin, p21, and p53 are controlled by HDACs, suggesting that HDACs may also be involved in a broad spectrum of cell signaling events regulated by these molecules. HDAC inhibitors have been shown to exhibit anti-neoplastic effect in many types of tumor cell lines as well as in vivo models. There is substantial preclinical evidence of synergistic induction of cancer cell death when HDAC inhibitors are combined with a diverse range of other targeted therapies or standard chemotherapeutic agents, demonstrating that HDAC inhibition may be more broadly effective in the treatment of cancer when integrated with other inhibitory activities. Thus, it was validated as a promising target in targeted cancer therapy strategies. Our ongoing effort is to explore novel HDAC inhibitors as effective anticancer agents using naturally occurring scaffold and knowledge-based design. Recently, we have achieved two aliphatic hydroxamates as pan-HDAC inhibitors: compound 2g fused with osthole derivative and compound 10k hybridized with the core of SAHA and LBH589; both compounds showed high potency against several HDAC isoforms. They also exhibited multiple significant cellular effects on cancer cells as well as effective antitumor activity in xenograft model, while did not cause significant side effects. Furthermore, using knowledge-based design and molecular docking analysis in HDAC8 co-crystal structure, we obtained an ortho-biphenyl N-hydroxycinnamide (6d) showed excellent enzyme inhibition and antiproliferative activity in various human cancer cell lines. We considered that structure optimization on compounds 2g, 10k, 6d may further improve their in vitro and in vivo pharmacological profile for the clinical studies. In this three-year project, we will combine synthetic chemistry, structure biology supported by Co-PI, Dr. Chang at Academia Sinica and biological evaluation performed by Co-PI, Prof. Guh at NTU to achieve our goal for lead optimization based on the results as described above. This study may help us to develop HDAC inhibitor as a potential agent for targeted cancer therapy or for other diseases related to the enzyme. Specific aim of the first year: Exploiting osthole-based aliphatic hydroxamate as a lead compound, we aim to use click chemistry for introduction 1,2,3-triazole ring into linker and to investigate whether such modification could improve the cytotoxicity against various human cancer cells and in vivo antitumor activity. Moreover, the structure-activity relationship (SAR) could be validated by using molecular modeling or co-crystallography. Specific aim of the second year: Based on our preliminary studies on ortho-biphenyl N-hydroxycinnamide, we aim to make modification to biphenyl group to increase the antiproliferative potency against several cancer cell lines, leading to construct the SAR. The cellular function involved in HDAC8 inhibition could be further clarified through the study. Specific aim of the third year: Owing to the effective antitumor activity of indole-based aliphatic hydroxamate, we aim to change the connecting constituent of linker and to see if such modification could improve in vitro cytotoxicity and in vivo pharmacokinetic profile. The cellular signaling associated with the inhibitor could be further investigated.