Structure-based inhibitor discovery for the development of new treatments against cancer

Ossama El-Kabbani and his group have just published the first high-resolution 3D structure of the complex between the drug target 20a-hydroxysteroid dehydrogenase and a potent active site inhibitor in the Journal of Medicinal Chemistry, currently the highest ranking journal in medicinal chemistry research.  An electronic copy of this publication can be found online at http://pubs.acs.org/journals/jmcmar/
 
The enzyme 20a-hydroxysteroid dehydrogenase, also known as AKR1C1, plays a major role in the metabolism of the hormone progesterone that is essential for the maintenance of pregnancy. Recent studies have also indicated that this enzyme is involved in the development of several human and rodent tumours, such as lung, endometrial, oesophageal, ovarian and breast cancers, and suggest that its over-expression in cancer cells is related to drug-resistance against several anti-cancer agents.
 
Ossama said "Together with our collaborators from Gifu Pharmaceutical University in Japan we were able to discover from a virtual screening-based approach several potent inhibitors of AKR1C1 that may be used as lead compounds for drug design. We then successfully grew the first crystals of the enzyme-inhibitor complex and solved its 3D structure at high-resolution using the method of X-ray crystallography.  We now have collaborations in place at the Monash Institute for Pharmaceutical Sciences to do structure-based design and synthesis of selective inhibitors with potential use as treatments against cancer and premature birth."