Largazole and Histones

I have a certain affection for things that affect epigenetic regulation. Hence my interest in a class of enzymes called histone deacetylases (HDACs). These are zinc-dependent hydrolases that cleave the acetate group off of the lysine residues on the N-terminal tails of H3 histones. The bottom line is that deacetylation of these proteins that DNA wraps around turns off gene expression. In some cancers, tumor supressor genes are turned off and application of HDAC inhibitors turns them back on causing the cancer cell to die its normal death. That is a simplistic description. It is actually much more complicated than that. A simple animation of this is provided on the Methylgene web site.

In January, the Luesch group from Florida reported (J. Am. Chem. Soc., 130 (6), 1806 -1807, 2008. 10.1021/ja7110064) the isolation and characterization of an antiproliferative natural product called largazole. They subsequently synthesized it and discovered it was an inhibitor for HDACs (J. Am. Chem. Soc., 130 (26), 8455–8459, 2008. 10.1021/ja8013727). The synthesis is pretty efficient encompassing 8 steps with an overall yield of 19%. That's not too bad. Andy Phillips, in Colorado, has just published another 8 step synthesis and have confirmed the Leusch findings (Org. Lett., ASAP Article, 10.1021/ol8013478 ). In addition they have done some NMR conformational studies to show the solution structure of this interesting molecule.

What I find very interesting about this story is that the compound looks so very similar to cyclic peptide HDAC inhibitors developed in Japan (FK228, link to PDF). The sulfur gets buried into the active site pocket to bind the catalytic zinc while the cyclic structure binds to the surface of the enzyme. Both are necessary for the nanomolar level of inhibition of Class I HDACs that are observed for these compounds. Knowing the structure of FK228, I would have immediately made the connection between largazole's antiproliferative effects and HDAC inhibition. The original isolation paper does not speculate on that which makes me wonder if the Leusch group only made this connection later. I presume so.

The way this story has unfolded reminds me that I need to search more broadly when I am looking for HDAC inhibitor structures. Just searching on the keyword 'hdac inhibitor' is not enough and probably misses some compounds that people haven't yet connected to HDACs.