Histone Deacetylase Inhibitors Equipped with Estrogen Receptor Modulation Activity

Abstract

We described a set of novel histone deacetylase inhibitors (HDACi) equipped with either an antagonist or an agonist of the estrogen receptor (ER) to confer selective activity against breast cancers. These bifunctional compounds potently inhibit HDAC at nanomolar concentrations, and either agonize or antagonize ERα and ERβ. The ER antagonist activities of tamoxifen-HDACi conjugates (Tam-HDACi) are nearly identical to those of tamoxifen. Conversely, ethynyl-estradiol HDACi conjugates (EED-HDACi) have attenuated ER agonist activities relative to the parent ethynyl-estradiol. In silico docking analysis provides structural basis for the trends of ER agonism/antagonism and ER subtype selectivity. Excitingly, lead Tam-HDACi conjugates show anticancer activity that is selectively more potent against MCF-7 (ERα positive breast) compared to MDA-MB-231 (triple negative breast cancer), DU145 (prostate cancer) or Vero (non-cancerous cell line). This dual-targeting approach illustrates the utility of designing small molecules with an emphasis on cell-type selectivity, not merely improved potency, working towards a higher therapeutic index at the earliest stages of drug development.

Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase

“…Approaches currently exploited to make this achievable include: i) using a non-hydroxamate ZBG 40 , ii) having a targeting group attached to the surface recognition group 19a , iii) making dual acting conjugates comprising a cytotoxic component and HDACi template 19a , and iv) using a prodrug approach 41 . Herein, we described compounds that potently and selectively inhibit COX-2 while also maintaining strong anti-HDAC activity.…”

“…Recently, there has been enormous interest in the development of dual-acting compounds comprising of an HDACi and another cytotoxic component 19 . In such compounds, one of the "warheads” is usually the surface recognition group (cap) of the HDACi (see pharmacophoric model in Figure 4a).…”

Synthesis and Structure–Activity Relationship of 3-Hydroxypyridine-2-thione-Based Histone Deacetylase Inhibitors

“…37, 38 Following the 3D energy minimization of the ligand by ChemBioDraw 3D, the docking was run in a 25 Å cubic space encompassing the active site, the binding pocket and its surrounding.…”

HDACs and HDAC Inhibitors in Cancer Development and Therapy

“…Numerous chemical hybrid molecules containing both HDACi activities and an additional anticancer module are under development, dual targeting HDACs and estrogen receptor (ER) (Tang et al 2015), retinoid X receptor (RXR) (Wang et al 2015), topoisomerase I/II (Guerrant et al 2013), 1α, 25- vitamin D (Lamblin et al 2010), oestrogen receptor (Gryder et al 2013), receptor tyrosine kinases (RTK) (Zhang et al 2013), tubulin (Zhang et al 2015b) or DNA methyltransferase (Shukla et al 2015), potentially leading to a rational efficacy in cancer therapy. Additionally, the hybrid of a nitric oxide (NO) donor and an histone deacetylase inhibitor has been developed and displayed outstanding antiproliferative activity in tumor cells (Duan et al 2015).…”