441061-33-2Relevant academic research and scientific papers
A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase
Lahav, Dani?l,Liu, Bing,Van Den Berg, Richard J.B.H.N.,Van Den Nieuwendijk, Adrianus M. C. H.,Wennekes, Tom,Ghisaidoobe, Amar T.,Breen, Imogen,Ferraz, Maria J.,Kuo, Chi-Lin,Wu, Liang,Geurink, Paul P.,Ovaa, Huib,Van Der Marel, Gijsbert A.,Van Der Stelt, Mario,Boot, Rolf G.,Davies, Gideon J.,Aerts, Johannes M. F. G.,Overkleeft, Herman S.
, p. 14192 - 14197 (2017)
Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source.
Pharmaceutically active piperidine derivatives
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, (2015/12/18)
Compounds of formula (I): wherein R represents various substituent groups, are useful as inhibitors of glucosylceramide synthase.
Identification of potent and selective glucosylceramide synthase inhibitors from a library of N-alkylated iminosugars
Ghisaidoobe, Amar,Bikker, Pieter,De Bruijn, Arjan C. J.,Godschalk, Frithjof D.,Rogaar, Eva,Guijt, Marieke C.,Hagens, Peter,Halma, Jerre M.,Van't Hart, Steven M.,Luitjens, Stijn B.,Van Rixel, Vincent H. S.,Wijzenbroek, Mark,Zweegers, Thor,Donker-Koopman, Wilma E.,Strijland, Anneke,Boot, Rolf,Van Der Marel, Gijs,Overkleeft, Herman S.,Aerts, Johannes M. F. G.,Van Den Berg, Richard J. B. H. N.
body text, p. 119 - 123 (2011/04/15)
Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promising target for combating type 2 diabetes. Iminosugars are useful leads for the development of GCS inhibitors; however, the effective iminosugar type GCS inhibitors reported have some unwanted cross-reactivity toward other glyco-processing enzymes. In particular, iminosugar type GCS inhibitors often also inhibit to some extent human acid glucosylceramidase (GBA1) and the nonlysosomal glucosylceramidase (GBA2), the two enzymes known to process glucosylceramide. Of these, GBA1 itself is a potential drug target for the treatment of the lysosomal storage disorder, Gaucher disease, and selective GBA1 inhibitors are sought after as potential chemical chaperones. The physiological importance of GBA2 in glucosylceramide processing in relation to disease states is less clear, and here, selective inhibitors can be of use as chemical knockout entities. In this communication, we report our identification of a highly potent and selective N-alkylated l-ido-configured iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.
