Development of small-molecule inhibitors targeting adipose triglyceride lipase (ATGL)

During the last decades it has been shown that a deregulated fatty acid (FA) metabolism is closely linked to the emergence of dyslipidemic and metabolic disorders.1 Adipose Triglyceride lipase (ATGL), is the rate limiting enzyme in triglyzeride metabolism in adipocytes strongly determining the concentration of circulating FAs.1,2 In absence of ATGL, increased insulin sensitivity combined with impaired glucose tolerance and resistance to cancer associated cachexia related to increased white adipose tissue (WAT) lipolysis and proteasomal muscle degradation is reported, which make ATGL a potentially interesting drug target. Recently we reported about the first potent inhibitor of murine ATGL (IC50 = 0.7 µM). Atglistatin reduces fatty acid mobilization in vitro and in vivo in mice, but surprisingly shows little activity against human ATGL despite high sequence similarity (>95%) in the active site.2,3 Based on structure-activity relationship (SAR) we have gained insight into the binding pocket of ATGL and used this knowledge for the synthesis of selective inhibitors of hATGL. [1] N. Mayer, M. Schweiger, M.C. Melcher, C. Fledelius, R. Zechner, R. Zimmermann, R. Breinbauer, Bioorg. Med. Chem. 2015, 23, 2904-1916. [2] A. Lass, R. Zimmermann, M. Oberer, R. Zechner, Prog. Lip. Res. 2011, 11, 14-27. [3] N. Mayer, M. Schweiger, M. Romauch, G. Grabner, T. Eichmann, E. Fuchs, J. Ivkovic, C. Heier, I. Mrak, A. Lass, G. Höfler, C. Fledelius, R. Zechner, R. Zimmermann, R. Breinbauer, Nat. Chem. Biol. 2013, 9, 785-787. [4] S. Eder, S. Schauer, C. Diwoky, H. Temmel, B. Guertl, G. Gorkiewicz, K. P. Tamilarasan, P. Kumari, M. Trauner, R. Zimmermann, P. Vesely, G. Haemmerle, R. Zechner, G. Hoefler, Science 2011, 333, 233-238.