Protein–protein interaction inhibitors get into the groove
In a recent ‘News and Analysis’ piece on Nature Reviews Drug Discovery, Asher Mullard, heralds the advancement in drug discovery efforts against Protein-protein interactions – “the unmined biology gold reserve”.
Protein-protein interactions (PPI) for a long time were considered unsuitable, or at least extremely hard for targeting by small-molecules. While for traditional target classes (Enzymes, GPCRs, Kinases) small molecules tend to bind in a deep pocket (often used to bind an endogenous substrate) that offers handles for a molecule to bind, the interfaces of PPIs were perceived as too large and featureless to design binders against.
This view of PPIs changed drastically with the discovery of ‘Hotspot’ residues at the interfaces of interacting proteins. These residues, a small subset out of the interface residues, are responsible for the majority of the binding energy and their interaction sites represent possible sites for small molecule binding.
A specific inhibitor of the interaction of human BRD4 first bromodomain with histones. (Filippakopoulos et al. (2010) Nature 468: 1067-1073) PDB id: 3MXF
What approaches then are currently taken to tackle this challenging class of drug targets? Prof. Jim Wells of UCSF (and founder of Sunesis), David Fry, a research scientist at Roche, and Nick Terrett, CSO at Ensemble offer some answers.
* Fragment based screens that detect weak binding of very small molecules (~150-250 Da – smaller than the average drug) can be used to assess the ‘druggability’ of a certain PPI. Thus enabling early identification of plausible PPI targets to focus on.
* The novel characteristics of PPIs offer, on the one hand, various new chemotypes and many possibly effective scaffolds to serve as inhibitors. On the other hand, this means that drug designers can’t rely on the old ‘go-to scaffolds’ as starting points – currently this means that each target is a fresh start, but the hope is that patterns will emerge as more data is collected – e.g. scaffolds that are effective against specific interface architectures.
* Exploring new areas of chemical space. Pharmaceutical screening libraries are biased towards know drug-like molecules space. Reported PPI inhibitors are larger and more rigid than one would expect for a drug-like compound. Indeed companies now expand the scope of their libraries (E.g. Forma Therapeutics’ screening library now approaches 1M compounds originating from ‘diversity-oriented synthesis’ aimed to explore novel regions of chemical space)
* As a side note Mullard mentions that peptides are more natural candidates for the inhibition of PPIs (a point I can not agree with more) but however suffer from poor cell permeability, a fact that did not stop various companies from pursuing them (including Aileron, Compugen, Polyphor, PeptiDream and Bicycle Therapeutics)
Mullard notes several ongoing PPI inhibitor pipelines that are working their way through the clinic, and there is broad consensus that PPIs are definitely worth to pursue from the biological point of view. However I wonder how much has this field progressed? 8 years ago to the month Wells published a (highly cited) review in the very same journal heralding the progress in the discovery of small molecules against PPIs (Small-molecule inhibitors of protein–protein interactions: progressing towards the dream). It seems the dream is yet to be achieved.
What do you think? Are we progressing still?
Mullard A (2012). Protein-protein interaction inhibitors get into the groove. Nature reviews. Drug discovery, 11 (3), 173-5 PMID: 22378255
Arkin MR, & Wells JA (2004). Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nature reviews. Drug discovery, 3 (4), 301-17 PMID: 15060526
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