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.
It is nice to see progress continues to be made against finding chemical matter for difficult targets. The terms druggable/undruggable get used a lot when discussing difficult targets and to me, using this ATAD2 program as an example, it seems the med chem community needs some additional language to more accurately describe the status. It is clear progress from an untractable target to a more tractable target has been made here, but to describe it as druggable is a stretch. Using druggable to refer to only targets where a drug is approved also feels over burdensome. Perhaps druggable should be reserved for targets when an asset enters the clinic and is first dosed to humans. Then how best to describe the current status of the ATAD2 target? Hit-able? Probably not as the term may raise a few eyebrows outside of the med chem community. Lead-able? Maybe. Other suggestions?
ReplyDeleteChris,
ReplyDeleteExcellent point. I like to refer to targets as Ligandable. The Vanderbilt work on ATAD2 from last year would have taken it from Unliganded to Ligandable. Going from Ligandable to Druggable is a HUGE stretch. I would support your suggestion that until something goes into the clinic it is not druggable.
We agree with you both, and in the paper we called it “ligandability” rather than “druggability”. We used libraries and arrays interchangeably, and the NMR was done by visual inspection – we find this the most reliable.
ReplyDeleteThere’s a followup to this paper that has just come out (J. Med. Chem. 2015, vol 58(15) p 6151-6178). It takes the optimization onwards a step or two, to compounds which match our goals at least as far as in vitro potency and selectivity. Hope you find this interesting, and thanks for blogging about us.
Nice work, and I agree about the term ligandability, which I think Alex Breeze and (former) AstraZeneca colleagues
ReplyDeletecoined in 2011.
Personally I think druggable should be reserved for something that is ligandable and also shows a positive effect in the clinic. By this standard BACE1 is ligandable but still not proven to be druggable, whereas BCL2 appears druggable.