Abstract 727: Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a diaryl template

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Designing single agents that act against multiple biological targets are of increasing interest and prominence. In recent years, an increasing volume of work has been published exemplifying the successful use of this strategy. Estrogen 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, although the inhibition of steroid sulfatase (STS) is an emerging new strategy as demonstrated by the promising results of STX64 (BN83495),1 the first STS inhibitor that entered clinical trials. While both aromatase and STS are targets for treating HDBC, it is reasoned that estrogen deprivation may be more comprehensively achieved by dual inhibition of both enzymes. To this end, the reversible aromatase inhibitory pharmacophore, which is principally a heme-ligating nitrogen-containing heterocycle, was thus introduced into a known sulfamate-based STS inhibitor to give a series of dual aromatase-sulfatase inhibitors (DASIs). Several compounds were found to be good aromatase or STS inhibitors individually. However, two compounds show exceptional dual in vitro potency in JEG-3 cells, inhibiting aromatase with IC50 values of 0.5 and 2.0 nM, and STS with IC50 values of 5.5 and 35 nM. Both compounds share the common structural feature of having a sulfamate group on one aryl ring, and a heterocycle and a H-bond acceptor on the other. At 1 mg/kg p.o., both DASIs reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. One of the compounds was found to be non-estrogenic and potently inhibit human carbonic anhydrase II (hCAII IC50 = 86 nM). A complex of hCAII with the inhibitor was crystallized and solved by X-ray crystallography. This class of DASI should encourage further development towards multi-targeted therapeutic intervention in HDBC. Ref 1: a) Stanway, S. J. et al. Clin. Cancer Res. 2006, 12, 1585-1592. b) Stanway, S. J. et al. Oncologist 2007, 12, 370-374. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 727.