A classical approach used in drug discovery is to use a small molecule to bind to a protein and thereby inhibit its function which is in some way implicated in a disease process. This approach frequently requires high levels of occupancy of the target protein for a prolonged period. To ensure the required occupancy, high levels of circulating drug are needed which can potentially cause undesirable effects and frequently toxicity. The consequence of this is that frequently molecules with narrow safety windows re progressed into the clinic and mechanisms are not fully tested.
A novel and very different strategy which is gaining momentum is to selectively degrade the disease related protein by selectively promoting its destruction via a cells endogenous biochemical pathway. An excellent example was recently published by Crews et al (Nature Chemical Biology 2015, 11, 611–617).
In this publication the authors describe the proteolysis targeting chimeras (PROTACs) method, whereby bidentate molecules are utilised which selectively bind to target (disease relevant) proteins and relevant ubiquitin ligases at the same time and thus leading to the selective ubiquitination of the undesired protein promotion of its degradation by the proteasome.
Two examples of PROTACs are described (figure 1), both contain a common fragment (shown in blue) which is a ligand of a protein (VHL) which selectively recruits E3 ligases. The common ligand is then linked via different flexible chains to compounds which potently and selectively bind to two different proteins involved in disease pathways. (b) contains a potent ligand for the oestrogen receptor ERalpha (in orange) and (c) a compound which potently binds the kinase RIPK2.
Looking at the compounds from a medicinal chemistry perspective, at first sight they appear to be very unattractive, being of very high molecular weight, highly polar and containing multiple rotatable bonds, yet they are active in cellular assays. Figure 2 clearly demonstrate a concentration dependent degradation of ERRa in MCF7 cells. The paper describes further experiments with both compounds in different cellular systems demonstrating both efficacy and specificity for the mechanism under investigation.
The data presented in this publication and those cited within clearly demonstrate the potential of this novel approach albeit at a very early stage and it will be interesting to see how far the methodology is able to go towards becoming a drug over the coming years. Of particular interest will be the developability profiles of such unexplored chemotypes and also the chronic safety implications of targeting the proteasome.
Blog written by Paul Beswick