crystal structures of three classes of non-steroidal anti-inflammatory drugs in complex with aldo-keto reductase 1c3晶体结构的三个类非甾体抗炎药在复杂aldo-keto还原酶1 c3.pdfVIP

Crystal Structures of Three Classes of Non-Steroidal Anti- Inflammatory Drugs in Complex with Aldo-Keto Reductase 1C3 1,2 3 3 3 4 Jack U. Flanagan , Yuliana Yosaatmadja , Rebecca M. Teague , Matilda Z. L. Chai , Andrew P. Turnbull , Christopher J. Squire2,3* 1 Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand, 2 Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand, 3 School of Biological Sciences, University of Auckland, Auckland, New Zealand, 4 Cancer Research Technology Discovery Laboratories, Wolfson Institute for Biomedical Research, London, United Kingdom Abstract Aldo-keto reductase 1C3 (AKR1C3) catalyses the NADPH dependent reduction of carbonyl groups in a number of important steroid and prostanoid molecules. The enzyme is also over-expressed in prostate and breast cancer and its expression is correlated with the aggressiveness of the disease. The steroid products of AKR1C3 catalysis are important in proliferative signalling of hormone-responsive cells, while the prostanoid products promote prostaglandin-dependent proliferative pathways. In these ways, AKR1C3 contributes to tumour development and maintenance, and suggest that inhibition of AKR1C3 activity is an attractive target for the development of new anti-cancer therapies. Non-steroidal anti-inflammatory drugs (NSAIDs) are one well-known class of compounds that inhibits AKR1C3, yet crystal structures have only been determined for this enzyme with flufenamic acid, indomethacin, and closely related analogues bound. While the flufenamic acid and indomethacin structures have been used to design novel inhibitors, they provide only limited coverage of