Design, Synthesis, and Biological Evaluation of Novel Deguelin-Based Heat Shock Protein 90 (HSP90) Inhibitors Targeting Proliferation and Angiogenesis

Abstract

Deguelin exhibits potent apoptotic and antiangiogenic activities in a variety of transformed cells and cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogues do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To determine the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its antiproliferative and antiangiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogues 54 and 69, the B- and C-ring-truncated compounds, exhibited excellent antiproliferative activities with IC(50) of 140 and 490 nM in the H1299 cell line, respectively, and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 μM).

Synthesis and Evaluation of a Novel Deguelin Derivative, L80, which Disrupts ATP Binding to the C-terminal Domain of Heat Shock Protein 90

“…As mentioned previously, we synthesized a series of structural deguelin analogs to develop lead compounds with enhanced efficacy and/or reduced toxicity compared with deguelin Chang et al, 2012). A detailed scheme and the L80 synthesis procedure are described in the Supplemental Material.…”

“…To evaluate the effect of L80 on the proliferation of lung cancer cells, MTT assays were performed as described previously (Oh et al, 2007;Chang et al, 2012). Cells (1-2 Â 10 3 cells/well in 96-well plates) were treated with increasing concentrations of L80 for 3 days.…”

Deguelin Analogue SH-1242 Inhibits Hsp90 Activity and Exerts Potent Anticancer Efficacy with Limited Neurotoxicity

“…On the basis of the established structure-activity relationship (SAR) of deguelin, we synthesized a series of potent deguelin analogues to identify a novel anticancer drug targeting Hsp90 (25). Among these compounds, we chose SH-1242, a B-and Cring truncated analogue ( Supplementary Fig.…”

“…S1). SH-1242 displayed potent inhibitory effects on HIF1a expression and viability of H1299 human NSCLC cells and on hypoxia-mediated retinal neovascularization and vascular leakage in a diabetic retina without developmental defects in zebrafish embryos (25,26). We first assessed the potency of SH-1242 against various human NSCLC cell lines.…”

“…However, despite deguelin's potency, its potential Parkinsonism-like neurotoxicity may be an obstacle to further clinical development. Hence, we have synthesized a variety of deguelin analogues; of these, SH-1242, a B-and C-ring truncated analogue (25), displayed a potent antiproliferative effect against human cancer cells (25) and suppressed hypoxia-mediated retinal neovascularization and vascular leakage in diabetic retinas by suppressing hypoxia-mediated upregulation of HIF1a and VEGF expression without any obvious toxicity (26). These promising effects imply the potential of SH-1242 as a lead candidate for developing Hsp90 inhibitors.…”