Pleasant Surprise

Epigenetics is big.  Wicked big.  How big?  This big.  Papers come from everywhere.  In this paper, an academic group from Minnesota, goes after SIRT2 with fragments.  SIRT2 is a type III HDAC that resides primarily in the cytoplasm that uses NAD+ as a co-factor (Figure 1).

Figure 1.  Biochemical Reaction of SIRT2

Sirtuins (there are seven) have a long history aready in pharma.  SIRT2 has been fingered as a potential treatment for Parkinson's Disease (PD) and other pathologies, including bacterial infection.  There are a nice range of available inhibitors for SIRT2.

Figure 2.  Known Sirtuin2 Inhibitors

Suramin, a drug originally made in 1916.  I think it was made by pouring hot sulfuric acid over naptha tar (but my chemistry may be off).  Of course, when I saw this I got my dander up and got ready both barrels.  [It also made me chuckle, because many moons ago I co-authored a paper on suramin against RANK-RANKL.  In that paper suramin blocked a PPI.]  In this paper suramin is highly selective for SIRT1 over SIRT2 and 3.  So, as my wife says, your mind is like a parachute, it only works when open.  So, let see what they did.

One of the known inhibitors is

First, they evaluated a SIRT5-suramin crystal structure, where suramin mainly occupies the peptide binding site and a sulfonate protrudes into the nicontinamide binding site.  With this, they came up with the following generic plan (Figure 3). In this case, the circled napthalene is close to the  nicotinamide binding site.  They proposed to merge/link nicotinamide compounds to the appropriate suramin-like moiety. 

Figure 3.  Merging Strategy for SIRT2 Inhibitors

So, my quibble, and its not a big one, but their molecules are big (20 heavy atoms or more).  Oh well, a fragment is in the eye of the beholder.  Dan would call this FADD maybe.  Well, how did they do, you ask?  Well, they were able to generate sub-micromolar compounds (64 being the best) (50 nM![edited]), with selectivity against SIRT1 and 3.  The MOA was competitive vs. substrate and noncompetitive vs. NAD+ (although they could not rule out uncompetitive).  It had low cytotoxicity.  YAY.  Yet, it only had moderate anti-cancer activtity.  Well, those two outcomes could still allow it to be a good PD compound.  But their data indicated that it would have a low probability for crossing the BBB. 

So, in the end, I was pleasantly surprised.  This ended up being nice work with a good breadth of work.  I don't know if this makes it into the "lead-like" space or will remain in the "tool" space, but I like to see this kind of work, especially from academic groups.