Magic Methyl and SBDD

As sites have closed down, we have seen a fair number of paper come out describing work at various sites.  Today's paper is another of these, from Roche, Nutley.  The target is Tankyrase, blogged previously here.  

This group started with a biochemical screen of their in house fragment library (here for analysis of their library) against both TNKS1 and 2.  This screen resulted in two compounds: 1. a pyranopyridone and 2. a benzopyrimidone (that looks like the first published TANK inhibitor).  

Figure 1.  Fragments identified from biochemical screen.

They were able to co-crystallize 1 with the TANKS2 and then were able to model 2's binding based upon the known inhibitor.  This pleasingly revealed both similarities and differences in the binding.  the main recognition elements are largely the same.  A big difference is that the phenyl maintains hydrophobic interactions that the cyano group does not. 

Figure 2.  TANKS2 X-ray structure with 1 (orange carbons) and 2 (yellow carbons). 

This lead to the obvious decision to merge the two fragments leading to fragment 3. This compound was reasonably potent (320 nM), however it should moderate to high clearance in an in vivo PK study. 

Compound 3. 

Then of course, the medchem kicks in aiming to decrease cLogP and increase solubility by focusing on two areas: the fused phenyl ring and the isopropyl side chain. This work was able to achieve their goals, but they also stumbled on a "magic methyl" (9) which improved potency 100 fold.  

9.  Magic methyl on fused phenyl ring.

This magic methyl works by sliding into a little pocket defined by three tyrosine residues. 

Figure 3.  Magic methyl binding mode. 

The t-butyl alcohol derivative of 9 had excellent properties: reasonable solubility, excellent permeability, stopped axin degradation in cells in a dose dependent manner, prevented mRNA production of beta-catenin dependent genes, and in mouse had satisfactory in vitro activity and PK profile.  

This is an excellent example of FBLG.  The magic methyl does exist and X-ray is a highly enabling technology.