Inhibiting the enzyme oestrone sulphatase (ES) could provide a novel therapeutic
for hormone dependent cancers, suggested Professor Barry Potter (University
of Bath). ES converted the stored form of oestrogen, oestrone sulphate, to the
active form, he said. Over the past few years, it had become evident that the
enzyme was a major contributor to cellular oestrogen levels: breast tumour cell
levels were often 10-fold higher compared with those in the plasma of the same
patient, he said.
Professor Potter described how a programme of synthesis had begun at the University
of Bath, leading to the development of a highly potent, “star” ES
inhibitor.
The compound, oestrone-3-sulphamate (EMATE), appeared to block the target irreversibly
although there was no precedent for sulphamate compounds to act in this way.
Several mechanisms could account for this, he commented.
Unfortunately, in preclinical development studies, EMATE was identified as a
“super oestrogen” being five-fold more potent than ethinyloestradiol:
it could no longer be considered a candidate for hormone dependent cancer, said
Professor Potter.
However, the drug development work had not been wasted as the sulphamate derivative
of oestradiol was now in phase II clinical trials as an orally available prodrug
for oral contraception or hormone replacement therapy.
The design of non-oestrogenic, irreversible ES inhibitors continued with the
development of derivatives of tricyclic coumarin sulphamates, said Professor
Potter. A “third” aliphatic ring, of varying size (3-15 carbons),
was attached to the two-ring coumarin nucleus at the 3,4 positions to mimic
the C and D rings of natural steroids. One compound, with a seven-carbon ring,
was now entering phase II clinical trials.