Oncology Drug Discovery and Women's Health Group
Overview
Professor Reed’s group has three primary areas of research: Drug discovery, women’s health and basic research into: hormone-dependent cancers of the breast, endometrium and prostate; HIF-1 alpha and carbonic anhydrase IX. Professor Reed and Dr Purohit pioneered the discovery and development of a new class drug for breast cancer therapy. The Phase I trial of STX64, a steroid sulphatase inhibitor, produced very encouraging results. In addition, other drugs and therapeutic targets have been identified for women’s health and additional oncological indications including ovarian, endometrial and prostate cancer. Research by this group has generated 14 publications in 5+ rated journals in the last 3 years and over 90 patents have been granted.
Based on the biological targets identified by the group, a medicinal chemistry programme was initiated in collaboration with Professor Barry Potter of Bath University which led to the formation of Sterix Ltd. In 2004 Sterix Ltd. was sold to the French pharmaceutical firm, Ipsen-Biomeasure. Ipsen continues to provide funding for the group.
Oncology Drug Design
The first drug target identified by Professor Reed and Dr Purohit was the Steroid Sulphatase (STS) enzyme which is responsible for the generation of active steroids from their inactive sulphate conjugates. Dr Atul Purohit synthesised the first STS inhibitor, oestrone 3-methylthiophosphonate (E1-MTP). Following a medicinal chemistry programme to synthesise structural mimetics of E1-MTP, STX64 was identified a lead drug candidate and has already been through a successful Phase I trial for hormone-dependent breast cancer, in collaboration with Professor Charles Coombes of Imperial College London. Decreases in circulating oestradiol, androstenedione, DHEA and androstenediol were found in patients treated with STX64. As the aromatase enzyme also contributes to oestrogen synthesis, the possibility of developing dual aromatase – sulphatase inhibitors (DASI) has been explored and a preclinical lead compound identified by the group, STX681.
Alternative pathways by which growth-stimulatory hormones can be synthesised include the hydroxysteroid dehydrogenases (HSDs), which are thought to play a role in both breast and prostate cancer. Our team is currently developing unique in vitro and in vivo models to evaluate early lead compounds for both our 17ß-HSD Type 1 and HSD Type 3 drug design programmes.
In addition to hormone-dependent cancer, a novel orally bioavailable microtubule disruptor / anti-angiogenic agent, STX140, active against hormone-independent tumours has been identified and characterised by Professors Reed's team. This agent is active in vivo in a wide range of tumour models including taxane-resistant, P-glycoprotein positive xenografts. STX140 is currently in pre-clinical development in conjunction with Ipsen and is envisaged to enter the clinic in late 2008.
The first ever data for a Steroid Sulphatase Inhibitor E1CH3PS (E1-MTP).
Women’s Health
HRT/OC
Natural oestrogens, such as oestradiol, cannot be used for hormone replacement therapy (HRT) as they undergo rapid inactivation, by oxidation of the 17beta-hydroxyl group, during intestinal absorption and transit through the liver. Oestrogen sulphamates, such as EMATE were identified as potent inhibitors of steroid sulphatase but possess potent oestrogenic properties. Oestrogen sulphamates are a new type of oestrogen which bind to carbonic anhydrase in erythrocytes and transit liver without undergoing first-pass inactivation. Because of this, there is virtual absence of hepatic oestrogenicity and the production of clotting factors. This may reduce the risk of adverse events associated with HRT / OC (oral contraception). A number of oestrogen sulphamate derivatives, modified at the C-17 position are being tested as prodrugs for HRT/OC use.
Endometriosis
Endometriosis is a major cause of pelvic pain and sub-fertility. Ectopic growth of endometrial tissue is oestrogen-dependent. In addition to ovarian oestrogen production, there is compelling evidence that local oestrogen synthesis in endometriotic lesions promotes disease progression and resistance to endocrine therapy. Previous studies have shown that ectopic lesions express aromatase, which converts androstenedione to oestrone, but the role of steroid sulphatase (STS), the enzyme responsible for the formation of oestrone from oestrone sulphate, in endometriosis is unknown. Hence, the regulation of STS expression and the consequences of STS inhibition on normal endometrial function are the focus of our investigations.
Basic Research
We currently have many on-going research projects of a more basic nature which stem from our drug discovery work. In prostate cancer we are assessing the role that different HSD enzymes play in driving tumour growth, as there is much controversy about which enzyme forms are important in hormone-dependent prostate cancer. Work is ongoing into how our microtubule disrupting agent inhibits angiogenesis and what role is played by the transcription factor HIF-1 alpha.
We are also undertaking research to understand the role of carbonic anhydrase IX (CAIX) in tumour progression and angiogenesis. As CAIX is a potential new drug target for many different tumour types, the pharmacophore present in many of the compounds we have developed has the potential to be a potent CAIX inhibitor.
