Abstract

Dual Aromatase-Steroid Sulfatase Inhibitors for Translational Oncology

Barry Potter, Professor, University Of Oxford

Many tumours are hormone-dependent with estrogens involved in growth and development. Cyp19 P450 aromatase aromatizes androgens into estrogens and aromatase inhibitors (AIs) are established clinical agents in oncology. In a newer approach we have pioneered the idea that steroid sulfatase (STS) inhibition may also attenuate estrogenic stimulation inter alia by blocking intracrine conversion of sulfated precursors in tumour cells. We designed the first steroidal STS inhibitor that reached phase II clinical trials. Inhibition via the aryl sulfamate pharmacophore occurs by a novel mechanism. Non-steroidal sulfamates are in vivo-active, orally bioavailable and sequestered by carbonic anhydrase in red blood cells. Tricyclic Irosustat first entered clinical trial in postmenopausal women with hormone-dependent breast cancer (HDBC), being potent and well-tolerated with ca 100% targeted tumour STS inhibition and stable disease was confirmed in phase II trials. We have also demonstrated applicability to other hormone-dependent diseases, eg androgen-dependent prostate cancer, endometrial cancer and endometriosis. Phase II trials in endometrial cancer patients show responses, stable disease and an advantageous safety profile. Trials in endometriosis, employing another inhibitor are ongoing. AI therapy is recommended to be extended for up to 10 years on the basis of 2016 clinical trial data. However, patients are at risk of relapse and there is evidence that chronic AI treatment may upregulate STS and related organic anion transporters in AI-resistant cells. HDBC thus may be more effectively treated by polytherapy, ie dual inhibition of aromatase and STS. New clinical trials reporting in 2016 have shown the first evidence of clinical efficacy for STS inhibition in early breast cancer and also explored Irosustat in combination with an AI, showing clinical benefit for patients already progressing on AIs. However, single agents against multiple drug targets are now highly topical. We originated the dual aromatase-sulfatase inhibitor (DASI) concept, demonstrating excellent activity of early lead candidates, with the best inhibitors being of low nM potency in vitro and potent in vivo on both targets For the next DASI generation core motifs of two classes were combined generating hybrid structures designed by combining the core components of two leading series, namely 4-((4-bromobenzyl)-[1,2,4]-triazol-4-ylamino)benzonitrile-based and a biphenyl-based series. Several compounds show markedly improved dual inhibitory activities in the picomolar range in JEG-3 cells eg IC50: aromatase, 15 pM; STS, 830 pM and IC50: aromatase, 18 pM; STS, 130 pM. These first examples of a new class of highly potent dual inhibitor should encourage further development toward multi-targeted therapeutic intervention in oncology and now, with the recent positive clinical data, are attractive candidates for clinical progression.