Binary and ternary crystal structure analyses of a novel inhibitor with 17β-HSD type?1: a lead compound for breast cancer therapy

摘要

pOestradiol is a well-characterized sex hormone that stimulates breast cancer and other oestrogen-related diseases. 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step in the synthesis of oestradiol and androstenediol in breast tumour tissue. The enzyme9s high expression and activity after simultaneous blockade of oestrogen receptors and inhibition of aromatase in the tumour shows the necessity for its inhibition as a requirement for breast cancer therapy. In the present paper, we report structures of the binary and ternary complexes of 17β-HSD1 with a new inhibitor Esub2/subB {3-[3′,17′β-dihydroxyestra-1′,3′,5′(10′)-trien-16′β-methyl]benzamide}, and the enzyme inhibition by the later. The ICsub50/sub value for Esub2/subB was determined to be 42 nM in T47D cells. Multiple interactions between Esub2/subB and the enzyme include hydrogen bonds and hydrophobic interactions, as well as π–π interactions. A kinetic study demonstrated that Esub2/subB inhibits the enzyme9s reduction forming oestradiol from oestrone, with a iK/isubi/sub of 0.9±0.15 nM. Such strong inhibition is in agreement with its extensive interaction with the enzyme, suggesting its potential as a lead compound for breast cancer therapy. In fact, this possibility is enhanced by its capacity for cell penetration similar to natural steroids. Such inhibitors that block oestrogen synthesis to suppress the sulfatase pathway producing oestradiol can be used in adjuvant therapies with oestrogen receptor blockade, opening a new orientation of breast cancer treatment./p