Exploiting Acridine Scaffold to Develop Novel Anticancer Agents Based on a Dual Target Strategy

Histone deacetylase (HDAC) inhibitors were validated as promising compounds for use in targeted cancer therapy. Although various FDA-approved HDAC inhibitors are clinical effective in treating hematologic malignancies, numerous clinical trials have indicated that they exhibited only limited anticancer activity against solid tumors. The combination of HDAC inhibitors with topoisomerase (Topo) inhibitors reportedly results in synergistic in-vitro and in-vivo antitumor activity. Thus, a hybrid molecule with activity dual targeting HDAC and Topo provides therapeutic advantages against cancer without any pharmacokinetic issues. Recently, we have achieved an aliphatic-chain hydroxamate WJ35435 by hybridizing a clinically used HDAC inhibitor SAHA scaffold and a Topo inhibitor DACA moiety. WJ35435 exhibited dual inhibitory activity against HDAC and Topo. Notably, WJ35435 had in-vitro and in-vivo anti-solid tumor activity that exceeded those of SAHA, without significant side effects. Although the lead compound WJ35435 was more potent than SAHA against HDACs and some of their isoforms, relative to camptothecin, a reported Topo I inhibitor, WJ35435 exhibited moderate Topo I inhibitory activity and its cytotoxicities were evident only for limited spectrum of solid tumor cells. Accordingly, the structural optimization of WJ35435, based on the results of its molecular modeling, may enhance its anti-Topo I activity, further improving its in-vitro and in-vivo pharmacological profiles for clinical purposes. In this three-year project, the synthetic chemistry, enzyme-based assay and molecular modeling that will be performed in our lab and the biological evaluation that will be supported by the Co-PI Prof. Jih-Hwa Guh at NTU will realize our goal of optimizing WJ35435. This work may support the development of dual HDAC-Topo inhibitors as potential anticancer agents. Specific aim of the first year: Exploiting the molecular docking results of WJ35435, we will modify specific positions of WJ35435 to generate three series of compounds and to investigate whether such modifications can improve their anti-Topo I activity and cytotoxicities against various human solid tumor cells in-vitro and in-vivo. The structure-activity relationship (SAR) of the WJ35435 derivatives will be elucidated. Specific aim of the second year: Based on the results of the molecular modeling that is combined with knowledge-based design, we will produce three series of compounds that have both DACA structure and known HDAC inhibitor scaffold. The pharmacological and computational profiles of the resulting compounds will be used to elucidate the SAR. Specific aim of the third year: Utilizing the molecular docking analysis and a click chemistry-based approach, we will develop triazole-linker- and DACA moiety-containing aliphatic hydroxamates and determine whether, in addition to Topo inhibition, the resulting series can target a specific spectrum of HDAC isoforms. These compounds will be biologically evaluated to determine their SAR.