Two for the Price of One?
Can multi-targeted drugs lead to improved treatments for Alzheimer’s disease and other illnesses?
Many, if not most, current drug discovery projects start out with the aim of finding a compound that can modulate a single target protein. However, in the last decade or so, there has been burgeoning interest in the practical application of the concept of polypharmacology, i.e., the idea that a single molecule can embody two, or perhaps more, distinct biological activities by design, and not just as accidental, and mostly likely unwanted, off-target activities. Thus, it has become more common to observe reports in the literature of “hybrid”, “multi-targeted”, “dual” or “bispecific” molecules for a variety of indications.
Such compounds may be attractive for several reasons, such as:
- Improved patient compliance – since fewer pills need to be taken
- Superior efficacy against complex diseases, e.g., disruption of multiple processes which sustain cancer growth
- Improved safety compared to single-target drugs
As one example of this polypharmacological approach, a recent paper has described the discovery of the first dual GSK3β inhibitor/Nrf2 inducer for the treatment of Alzheimer’s disease (AD). In this paper, a team of academic scientists from Spain and UK worked to design compounds with neuroprotective and anti-inflammatory capabilities. The combination of GSK3β inhibition and Nrf2 induction in one molecule aims to decrease tau hyperphosphorylation, reduce oxidative stress and diminish chronic neuroinflammation, all of which are major pathological hallmarks of AD. This is by far from the only instance of a multi-target strategy being adopted to tackle AD as this review article makes clear.
The multi-target strategy has also been adopted in other therapeutic areas. For instance, in the search for improved treatments for chronic obstructive pulmonary disease, there has been great interest in a class of compound known as MABAs (muscarinic antagonist combined with beta-2 receptor agonist) which combine two well-known pharmacologies in a single molecule.
Elsewhere, in the realms of oncology, researchers are experimenting with the multi-target inhibition of cancer-associated kinases (“intrafamily polypharmacology”) as well as multitarget inhibition of kinases and targets belonging to different families, such as bromodomains—so-called “interfamily polypharmacology”.
Likewise, in seeking to further the treatment of pain and inflammation, the simultaneous inhibition of COX and FAAH activities with designed multitarget agents is being pursued with pre-clinical studies suggesting that such agents may offer superior anti-inflammatory efficacy combined with reduced toxicity.
Finally, in the field of metabolic disease, medicinal chemists have just reported chemical compounds that exhibit angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 4 (DPP-4) activities. Also in this area, the big pharma company Sanofi has teamed up with a UK start-up called Exscientia to discover and develop bispecific small molecules that treat diabetes. Interestingly, the approach taken involves the application of artificial intelligence (AI) techniques (the subject of a previous Eureka blog post).
While it is unlikely that we will see the end of “one target, one molecule” drug discovery projects, it seems that the era of multi-targeted compounds is well and truly with us and it will be fascinating to watch the progress of early exemplar compounds through the clinic in the coming years.
Design of Hybrid Molecules for Drug Development, Decker, M. (Ed.), Elsevier, 2017.
Anighoro, A.; Bajorath, J.; Rastelli, J. Polypharmacology: Challenges and Opportunities in Drug Discovery. J. Med. Chem., 2014, 57, 7874–7887. DOI: 10.1021/jm5006463
Peters, J.-U. Polypharmacology – Foe or Friend? J. Med. Chem., 2013, 56, 8955–8971. DOI: 10.1021/jm400856t
Polypharmacology in Drug Discovery, Peters, J.-U. (Ed.), John Wiley & Sons, 2012.