The A3-3 project - Inhibitors of hGST A3-3 for treatment of steroid hormone dependent diseases
Indication: cancer (prostate cancer and breast cancer)
Targeted mechanism: glutathione transferase A3-3-dependent steroid hormone synthesis
Founding researcher: Professor Bengt Mannervik, Department of Biochemistry and Organic Chemistry, Uppsala University.
Background
Prostate cancer and breast cancer are two major forms of malignant disease, which affect a significant proportion of the population. Tumor growth in both cases is often dependent on steroid hormones and an important therapeutic approach involves ablation of hormone production and blockage of the hormone receptor. The present project is using glutathione transferase (GST) A3-3 as a new target for chemotherapy, based on its contribution to double-bond isomerization in steroid biosynthesis.
Steroid hormone biosynthesis proceeds from cholesterol to androgens (e. g. testosterone and dihydrotestosterone) and estrogens (e. g. progesterone and estradiol) via a series of metabolic intermediates. An obligatory step in both pathways leading to production of the respective hormones involves the isomerization of the A5-double bond to the A4-double-bond in the steroid structure.
Glutathione transferases, GSTs, are traditionally regarded as detoxication enzymes but several GSTs are also involved in the metabolism of other cellular substrates. Professor Bengt Mannervik at the Department of Biochemistry and Organic Chemistry, Uppsala University, has discovered that GST A3-3 plays an important role in double-bond isomerization of steroids in hormone biosynthesis and the catalytic efficiency of GST A3-3 is 200-fold higher than the steroid isomerase activity of 3-hydroxysteroid dehydrogenase. The enzyme shows high catalytic activity in the isomerization of both 5-androstene-3,17-dione and 5-pregnene-3,20-dione and has a selective tissue distribution being expressed in steroidogenic organs such as testis, ovary, placenta and the adrenal gland, but not in significant amounts in other tissues such as liver, thymus, skeletal muscle and brain. This altogether suggests a significant role for GST A3-3 in the biosynthesis of steroid hormones.
Current status
The A3-3 project was initiated at Actar in 2007 in collaboration with Professor Mannervik. The project relates to the use of GST A3-3 as a drug target for treatment of steroid hormone dependent diseases, such as prostate and breast cancer. High throughput screening of compounds, preferably pharmaceutically acceptable compounds, that inhibit the activity of GST A3-3, is being undertaken at Actar’s facilities. The first phase of the screening process has been finished and selected hits transferred to the next steps of evaluation.