Richard H. Peters

A novel dual-target steroid sulfatase inhibitor and antiestrogen: SR 16157, a promising agent for the therapy of breast cancer

Endocrine therapy is the ideal treatment choice for estrogen receptor α (ERα)-positive breast cancer patients. Principal used therapies target either the ERα e.g. by selective ERα modulators (SERMs) such as tamoxifen or target estrogen biosynthesis with aromatase inhibitors. Steroid sulfatase (STS) plays a crucial role in formation of compounds with estrogenic properties, converting inactive sulfate-conjugated steroids to active non-conjugated forms. Steroid sulfates are considered as a reservoir for active steroids due to their prolonged half-life and increased concentration in plasma. STS is present in several tissues including the breast, and the STS the mRNA level and enzyme activity is significantly increased in ERα-positive breast tumors. Inhibition of STS is therefore a new approach for decreasing estrogenic steroids that stimulate breast cancer. The novel dual-acting compound SR 16157 is designed as a sulfamate-containing STS inhibitor that releases a tissue-selective SERM SR 16137. Use of a dual-target STS inhibitor and SERM represents a new strategy in the treatment of hormone-dependent breast cancer. In this study, we tested the potential of SR 16157 and SR 16137 on STS activity, cell growth and ERα function in MCF-7 breast cancer cells. We confirmed that the dual-target compound SR 16157 exerts STS inhibition and antiestrogenic effects. SR 16157 was a highly effective growth inhibitor, being 10 times more potent than the antiestrogens SR 16137 and tamoxifen. Relative to tamoxifen, SR 16137 displays profoundly improved ERα binding affinity and antiestrogenic effects on expression of estrogen-regulated genes. Thus, the dual-target SR 16157 is possibly a promising new treatment alternative, superior to tamoxifen.

Synthesis and testing of 17aβ-hydroxy-7α-methyl-d-homoestra-4, 16-dien-3-one: a highly potent orally active androgen

Abstract The title compound, 17aβ-hydroxy-7α-methyl- d -homoestra-4, 16-dien-3-one (3), was synthesized in five steps (17% overall yield) from 7α-methylestrone methyl ether (5) and was found to possess oral androgenic activity, in excess of other known androgens, without using 17α-alkyl substitution. (Steroids 55 :59–64, 1990)