Hybrid Dual Aromatase-Steroid Sulfatase Inhibitors with Exquisite Picomolar Inhibitory Activity

Abstract

Single agents against multiple drug targets are highly topical. Hormonedependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS), and several dual aromatase-sulfatase inhibitors (DASIs) have been recently reported. The best compounds from two leading classes of DASI, 3 and 9, are low nanomolar inhibitors. In search of a novel class of DASI, core motifs of two leading classes were combined to give a series of hybrid structures, with several compounds showing markedly improved dual inhibitory activities in the picomolar range in JEG-3 cells. Thus, DASIs 14 (IC 50 : aromatase, 15 pM; STS, 830 pM) and 15 (IC 50 : aromatase, 18 pM; STS, 130 pM) are the first examples of an exceptional new class of highly potent dual inhibitor that should encourage further development toward multitargeted therapeutic intervention in HDBC.KEYWORDS: Hybrid, dual inhibitors, aromatase, sulfatase, cancer E strogen deprivation has been an effective therapeutic intervention for hormone-dependent breast cancer (HDBC). One established and clinically proven approach involves the inhibition of the aromatase enzyme, 1-3 although the inhibition of steroid sulfatase (STS) is an emerging new strategy, as demonstrated by promising results for STX64 (Irosustat, BN83495), [4][5][6] the first STS inhibitor that entered clinical trials. Since both aromatase and STS are targets for treating HDBC, it has been reasoned that estrogen deprivation may be more comprehensively achieved by dual inhibition of both enzymes.Designing single agents that act against multiple biological targets is of increasing interest and prominence. In recent years, an increasing volume of work has been published exemplifying the successful use of this strategy. [7][8][9][10][11][12][13][14][15][16][17] We have pioneered this approach to augment our strategy directed at the first-in-class clinical target of STS inhibition and successfully developed three series of single agent dual aromatase and sulfatase inhibitors (DASIs) that are sulfamate derivatives of the nonsteroidal aromatase inhibitor (AI) 4-((4-bromobenzyl)-[1,2,4]-triazol-4-ylamino)benzonitrile (1) (e.g., 2 and 3), 18-20 letrozole 4 (e.g., 5), 21,22 and anastrozole 6 (e.g., 7) (Figure 1). 23 The design of these DASIs shares a common principle of engendering the irreversible STS inhibitory pharmacophore (ie. an aryl sulfamate ester, ArOSO 2 NH 2 ) into a clinical or experimental AI with minimal structural change incurred on the original scaffold in order to retain and maximize aromatase inhibition. More recently, a different design approach was employed. A series of biphenyl-based DASIs was developed as a result of incorporating the reversible aromatase inhibitory pharmacophore, which is principally a heme-ligating nitrogen-containing heterocycle, into a known sulfamate-based STS inhibitor (e.g., 8 and 9, Figure 1). 24 On evaluating the lead candidates from these four structural classes of DASI, all of them showed in vitro and in vivo dual inhibito...

Synthesis and Structure–Activity Relationship Studies of Derivatives of the Dual Aromatase–Sulfatase Inhibitor 4‐{[(4‐Cyanophenyl)(4H‐1,2,4‐triazol‐4‐yl)amino]methyl}phenyl sulfamate

“…They all inhibit STS with IC 50 values ranging between 20 and 44 n m . We have demonstrated repeatedly in previous SAR studies that the STS inhibitory activity of an aryl sulfamate can generally be increased by lowering the p K a value, and hence improving the leaving group ability, of its parent phenol 22–25, 27–31, 39. Because of the electron-withdrawing effect on the sulfamate group exerted by the halogens at the m , m ′-position, the p K a values of parent phenols 12 b and 18 c are predicted to be between 0.4 and 1.0 log units lower than those of phenols 3 a , 4 a , 11 c , and 17 c (as calculated by ACD/Labs v11.02 and based on comparison between respective mono- and dihalogenated para -cresols).…”

“…Briefly: 1) derivatives of the nonsteroidal AI 4-{(4-bromobenzyl)-[1,2,4]triazol-4-ylamino}benzonitrile (e.g., 2 – 5 , Figure 1);22–25 2) derivatives of letrozole (e.g., 6 , Figure 1);26–28 3) derivatives of anastrozole (e.g., 7 , Figure 1);29 4) derivatives based on a biphenyl template (e.g., 8 , Figure 1);30 and 5) a series of compounds with a hybrid structure of experimental DASIs (e.g., 9 , Figure 1). 31 Herein we report the further expansion of the series of DASIs 2 – 5 . Inhibitory activities of new candidates against aromatase and STS were evaluated in JEG-3 cells, and structure–activity relationships (SAR) are discussed.…”

Molecular Simulations of Aromatase Reveal New Insights Into the Mechanism of Ligand Binding

“…Other aromatase inhibitors are also currently in development for clinical application or for use as chemical probes in research, utilizing novel scaffolds and mechanisms of action. 7–13 …”

Estrogen O-sulfamates and their analogues: Clinical steroid sulfatase inhibitors with broad potential

“…In contrast, Letrozole inhibited the growth of MCF-7 AROM tumours but not MCF-7 STS tumours, and the inhibition pattern of Irosustat was the reverse of this [95]. Further derivatives of YM511 based around a biphenyl template (Compounds B-D) are, in an in vitro inhibition assay in JEG-3 cells, potent inhibitors of both enzymes with AR IC 50 s of 0.15 nM, 0.015 nM and 0.018 nM, respectively, and STS IC 50 s of 2.3 nM, 0.83 nM and 0.13 nM, respectively [96,97].…”