Epigenetics is big. We keep on beating that drum. Just to prove it, today's paper is on a target we have talked about before: ATAD2. That previous paper was unsatisfying: leading to my summary: "if you throw enough fragments at a target you can find a few that bind." Today's entry from GSK has produced the first micromolar inhibitors of ATAD2.
As noted previously, ATAD2 is "undruggable" or at least VERY difficult to find chemical matter against. To add to the difficulty, the BET activity needs to be minimized. With that in mind, they set a high threshold of activity (pIC50 greater than7) and 100 fold selectivity against BRD4 (a representative BET domain). The ATAD2 site is more polar and flexible than BET. The authors felt that this would be exploitable to create selective molecules. To address ATAD2 they started with Ac-K mimics from previous BET work. They supplemented this with diverse cores not represented. One such array (which I read as libraries, somebody correct me if I am wrong) was based on the cpd 1,
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| Cpd 1. |
which is similar to the chemotypes discussed last year. A crystal structure of 1 was solved, confirming that it bound as expected.
Additional arrays were made around this core and tested in a TR-FRET assay. 30,000 compounds gave a 0.25% hit rate. Confirmation was performed by HSQC NMR. A subset of compounds interacted at the Ac-K site based upon comparison to compounds with known binding modes. In this case, the peak that shifted upon binding were the same. I would like to know if this was by visual inspection of spectra or if it was accomplished using PCA, or similar method. It probably doesn't matter, but intrigues the NMR jock in me.
In rounds of medchem and X-ray confirmation, they were able to drive the potency against ATAD2 to the single digit micromolar. The ligand efficiencies were maintained right around 0.30. 
Compound 57 (R=4-Me) and 60 (R=4-OMe) had the "best balance of ATAD2 and BET activity". These compounds were also active in a cell-based assay known to be sensitive to BET inhibitors. However, there is no selectivity. ATAD2/BET pIC50 for 57 was 1.1 and 60 was 1.0. So, despite the selectivity threshold they developed, these compounds are not selective. Despite that, I think this paper shows that the aphorism Undruggable =Undone is true.
Compound 57 (R=4-Me) and 60 (R=4-OMe) had the "best balance of ATAD2 and BET activity". These compounds were also active in a cell-based assay known to be sensitive to BET inhibitors. However, there is no selectivity. ATAD2/BET pIC50 for 57 was 1.1 and 60 was 1.0. So, despite the selectivity threshold they developed, these compounds are not selective. Despite that, I think this paper shows that the aphorism Undruggable =Undone is true.
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