PROTAC is definitely an exciting strategy. It is still very early pre-clinical. Looks like Arivas' most advanced pipeline candicates are ARV-110 and ARV-471 for androgen receptor degradation in prostate cancer and estrogen receptor alpha in breast cancer, respectively. BET/BRD PROTACs are not in the currently listed Arvinas pipeline. ARV-110 for androgen receptor is the most advanced. Arvinas is planning IND filing H2 2019 and Phase 1 start Q1 2019 for ARV-110. No clinical timeline on a BET/BRD PROTAC.

This Cell Chemical Biology paper describes PROTAC in a fairly simple way: "Proteolysis-targeting chimeras (PROTACs) are small molecules consisting of a targeting ligand (warhead) for a protein to be degraded, an E3 ubiquitin ligase recruitment ligand, and a chemical linker connecting the two ligands. Upon PROTAC-mediated heterodimerization of the two bound proteins, the target protein is ubiquitinated and degraded by the proteasome."

A figure in this ACS Chemical Biology paper portrays the above description beautifully. One part of the PROTAC molecule binds to the target protein (i.e. a BET protein like BRD4). This part of the molecule could potentially be a pan- or bromodomain-selective BET inhibitor like JQ1, OTX015, RVX-208, ZEN-3694, or another small molecule. The other part of the PROTAC molecule, such as the VHL binder (there are others too), recruits the cellular E3 ubiquitin ligase machinery. These two parts are connected/tethered to one another. So when the PROTAC molecule binds to its target protein (i.e. BET protein BRD4), the VHL binder is right there too and results in ubiquitination of BRD4. Ubiquitinated proteins are marked for degradation by the proteasome. 

So unlike reversible chemical inhibition by a small molecule BET inhibitor that binds to a the bromodomain of a BET protein like BRD4, the PROTAC strategy actually degrades/eliminates the BET protein. In both cases, BET bromodomain binding to to acetylated lysines of histones is prevented. In the case of PROTAC the entire BET protein is degraded, but in the case of small molecule BET inhibitors the BET protein is still there. This difference in the strategy could result in different outcomes. 

Another strategy recently published by Zenith is the use of covalent (irreversible) BET inhibitors "that target a methionine in the binding pocket by attaching an epoxide warhead to a suitably oriented non-covalent inhibitor." This isn't exactly the same at PROTAC, but similar in that both result in a more durable BET protein inhibition as compared to reversible inhibitors. A big difference is that these covalent inhibitors exemplified by Zenith may result in longer term protein inhibition without degrading the BET protein.

As with any new compound/new strategy there are pros and cons:

Is it amenable to oral dosing? There is literature out there on subcutaneously administered BET protein PROTACs, but have any oral compounds been developed? If daily dosing is required, oral is a preferable route than subcutaneous injections.

Is the tissue distribution the same? PROTACs are bigger than just small molecule BET inhibitors. Does it still get to the desired tissue(s) at the same levels and distribution pattern as the non-PROTAC inhibitor?

Is PROTAC degradation resulting in the same type of gene expression changes and desired clinical outcome as reversible (or irreversible) small molecule inhibitors that do not cause protein degradation? 

Are there additional side effects and adverse outcomes with protein degradation as opposed to small molecule inhibition without degradation? 

PROTAC is definitely worth keeping an eye on. Lots of potential. But protein degradation isn't the right solution to all clinical needs. For example, the beauty of RVX-208/apabetalone is that it preferentially inhibits bromodomain-2 (BD2) as opposed to bromodomain-1 (BD1) of BET proteins. However, a PROTAC version of apabetalone would end up degrading the entire BET protein that contains BD1 and BD2. So one would lose selectivity once the protein is degraded.

I hope this helps. Thanks for brining this up Topcoin.

BearDownAZ