Hot topics: Synthesis and SAR for depsipeptide natural products as selective G protein inhibitors

Posted on October 19, 2016 by guidetopharmacology — Leave a comment

A team including the Gloriam Group at the University of Copenhagen (also the home of GPCRDB) have paper out in Nature Chemistry reporting the first total synthesis of YM-254890 and FR900359 [1] . These are related cyclic depsipeptide natural products that specifically and potently inhibit the Gq subfamily of G proteins, a relatively rare but useful and pharmacological property [3]. By a combination of solution and solid-phase approaches the team generated sufficient YM-254890 and FR900359 material for confirmation of the structures , pharmacological characterisation and the synthesis of ten new analogues of YM-254890 for SAR analysis. The paper also includes docking studies based on the X-ray crystal structure of YM-254890 in PDB 3AH8 [3]

[1] Xiong et al. (2016). Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors. Nat Chem, advance online publication, doi:10.1038/nchem.2577

[2] Schrage R, et.al. (2015) The experimental power of FR900359 to study Gq-regulated biological processes. Nat Commun. 14;6:10156. doi: 10.1038/ncomms10156, PMID 26658454

[3] Nishimura A. et. al.(2010) Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule. Proc Natl Acad Sci; 107(31): 13666–13671. doi: 10.1073/pnas.1003553107, PMID 20639466

The two key potent ligands from the paper are included in the new GtoPdb release 2016.4. Details of this particular curation exercise are given in this blog post.
http://guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9335