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The last few years have witnessed a paradigm shift of the scientific community regarding the "one drug, one target, one disease" philosophy that have researchers focused on one specific biological target with high affinity and selectivity towards a molecule of interest, hoping to maximize efficacy and minimize side-effects1. Nowadays, it is generally acknowledged that one drug can have multiple targets that will affect various biological processes in different ways. Multi-target drug discovery is part of a concept called polypharmacology. When unintended, polypharmacology can be very dangerous because of unpredictable side-effects. Thus, a lot of drugs are regularly withdrawn from the market, mostly due to their toxicities.
For instance, Troglitazone (TGZ), an antidiabetic and anti-inflammatory drug prescribed for patients with diabetes mellitus type 2, was removed from the market when it was reported to be linked to hepatitis. Originally developed mostly for its PPARs (peroxisome proliferator-activated receptors) activation properties, TGZ’s implication with other mechanisms of action was afterward discovered. Mechanisms of troglitazone-induced hepatotoxicity have been characterized as formation of reactive metabolites, oxidative stress, mitochondrial toxicity, bile acid accumulation and mitochondrial permeability transition. 2,3.
On the other hand, anticipating these potential side-effects and managing polypharmacology can lead to successful outcomes. Many papers published these past 10 years suggest that more effective and safer drugs can be developed with polypharmacology approaches.1,4,5
Extracted from Polypharmacolgy – Foe or Friend? J Med Chem. 2013 Nov 27;56(22):8955-71. Peters JU
That’s why polypharmacology has a major importance today in the drug discovery and development process and represents a real challenge for the pharmaceutical industry.
There are different approaches in polypharmacology; it goes from drug combination with two or more drugs that independently have only one specific target, to multi-target drugs where one molecule acting on two or more targets is administered. The risk with combination therapies is that the use of multiple drugs introduces problems with pharmacokinetics, drug-drug interaction, toxicity and patient compliance. Multi-target drugs usually present a higher safety profile.
Different strategies to identify or design multi-target drugs can be used. Among them:
- The identification of the relevant targets for a given disease followed by screening strategies to fish the molecules with the expected protein target profile
- or the identification of the targets of the most promising molecules following a disease-relevant screening campaign.
The objective is to bring information to elucidate the molecule's mechanism of action in relation to complex protein networks and to understand how it can impact one or several disease molecular pathways.
Hybrigenics ULTImate YChemH target deconvolution platform is set up to deliver this kind of information with a focus on the direct interactants. This is a good starting point to move further in the investigation instead of using a list of hundreds potential target hits.
Multi-target drug discovery is a complex approach but the investment is worth it, and lot of great opportunities can arise through polypharmacology.
Furthermore, it is generally accepted that such complex therapeutic approaches is particularly adapted for intricate multifactorial pathologies, such as cancers, metabolic diseases, cardiovascular diseases, and neurological diseases 4, 6. Indeed, these diseases generally involve complex networks of proteins that can be addressed to improve therapies.
For instance in oncology, kinases are recognized as good targets for cancer treatments because they are involved in important signaling functions. Several multi-target tyrosine kinase inhibitors have been developed in the recent years. For example, Nintedanib (BIBF-1120, Vargatef®, Ofev®), is a triple kinase inhibitor targeting the vascular endothelial growth factor receptor (VEGFR), the fibroblast growth factor receptor (FGFR) and the platelet derived growth factor receptor (PDGFR). 7 It has been approved by the FDA in 2014 and is used to treat idiopathic pulmonary fibrosis (IPF). It can also be used in the treatment of Lung cancer. Recent studies show that Nintedanib has a good safety profile with most advert effects manageable without impacting its efficacy 8. More studies are still going to investigate the possible use of Nintedanib coupled with other drugs to treat other kind of cancer such as gastrointestinal stromal tumors or ovarian cancers.
Another interesting possibility of polypharmacology is for drug repositioning or drug repurposing 9, 10, 11. By identifying new on and off-targets of well-known therapeutic molecules, it is possible to find new indications and new uses of these drugs for other diseases. Repurposing is attractive and pragmatic given the substantial cost and time requirements for drug development. There are many examples in the literature. For exemple, optimization of troglitazone derivatives as potent anti-proliferative have been described 12.
Another exemple, in neurodegenerative diseases, Safinamide was originally developed as an anticonvulsant agent and approved in March 2017 as an add-on treatment to levodopa for Parkinson Disease thanks to its particular multi-target profile.13 It combines dopaminergic effects, including selective and reversible MAO-B and dopamine reuptake inhibition, along with non-dopaminergic properties, i.e. blockade of voltage-dependent Na+ and Ca2+ channels and consequent inhibition of glutamate release.
Distribution of the new molecular entities (NMEs) approved from 2015 to 2017, organized according to the different classes of NMEs
Extracted from Ramsay, R., Popovic‑Nikolic, M., Nikolic, K., Uliassi, E., Bolognesi, M., A perspective on multi‑target drug discovery and design for complex diseases. Clin. Trans. Med. 2018, 7(1), 3.
As mentioned before, identifying the on and off-targets of a molecule of interest is a key step for any polypharmacology approaches. Traditionally, studies focus on a list of safety-relevant and validated targets to test, but it’s not exhaustive and doesn’t allow to explore all the possibilities or new targets. Many polypharmacological drugs are discovered only by chance when the molecule is already on the market and some great therapeutic avenues may never be uncovered because the drug’s targets remain unknown or only partially understood.
Hybrigenics’ ULTImate YChemH is a drug target deconvolution method that is direct, in vivo and highly sensitive. It allows us to find all the protein partners of your molecule of interest, using it as a bait to screen one of our highly complex protein domain libraries.
These unique libraries are prepared from a given tissue, primary cultures or a cell line of interest, which enables whole proteome screening in an unbiased manner. We can test more than 80 million interactions at the same time ensuring an exhaustive screening of the library. Furthermore, each interaction is tested individually. That means we can find all the targets of a molecule of interest for a given sample also unexpected targets whether it’s a strong or weak interaction. In addition, we can identify precisely the interacting domain of the target protein with the molecule which provides very useful information to optimize further analysis. Some drug discovery approaches can also take advantage of such finding. These key advantages put ULTImate YChemH as one of the best tool for drug target deconvolution on the market and a strong ally for those who want to design an efficient polypharmacology strategy.
It is most likely that the interest for polypharmacology will increase in the coming years to bring optimized drugs to the market, more efficient and less prone to toxicity. However, designing a successful polypharmacology strategy remains a challenge and several strategies are being developed 15, 16. Those who will take the time to properly identify their molecule’s targets will certainly gain a major advantage to uncover the pathways that lead to success.
1. Reddy, A.S.; Zhang, S. Polypharmacology: drug discovery for the future. Expert Rev Clin Pharmacol. 2013, 6 (1), 41-47.
2. Manautou, J. E., Campion, S. N., Aleksunes, L. M. Regulation of Hepatobiliary Transporters during Liver Injury. Comprehensive Toxicology, 2010, 175–220.
3. Segawa M., Sekine S., Sato T., Ito K., Increased susceptibility to troglitazone-induced mitochondrial permeability transition in type 2 diabetes mellitus model rat, J Toxicol Sci. 2018, 43(5), 339-351.
4. Peters, J.-U., Polypharmacolgy – Foe or Friend? J Med Chem., 2013, 56(22), 8955-8971.
5. Anighoro, A., Bajorath, J and Giulio Rastelli, G., Polypharmacology: Challenges and opportunities in Drug Discovery, J Med Chem., 2014, 57, 7874−7887.
6. Multi-Target Drugs: The Trend of Drug Research and Development PLoS One. 2012; 7(6): e40262 Jin-Jian Lu, Wei Pan, Yuan-Jia Hu, and Yi-Tao Wang.
7. Wollin, L., Wex, E., Pautsch, A., Schnapp, G., Hostettler, K.E., Stowasser, S., Kolb, M. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J, 2015; 45, 1434–1445.
8. Roth, G.J., Binder, R., Colbatzky, F., Dallinger, C., Schlenker-Herceg, R., Hilberg, F., Wollin, S.-L., Kaiser, R. Nintedanib: From Discovery to the Clinic J. Med. Chem. 2015, 58, 1053−1063.
9. Liu, X., Zhu, F., X. Ma, H., Shi, Z., Yang, S. Y., Wei, Y. Q., Chen., Y. Z. Predicting targeted Polypharmacology for Drug Repositioning and Multi-Target Drug Discovery. Curr. Med. Chem., 2013, 20, 1646-1661.
10. MTalevi, A. Drug repositioning: current approaches and their implications in the precision medicine era, Expert Rev. Precision Med. Drug Dev., 2018, 3(1), 49-61.
11. Nishimura, Y., Hara H., Editorial: Drug Repositioning: Current Advances and Future Perspectives. Front. Pharmacol., 2018, 9,1068.
12. Bordessa, A., Colin-Cassin, C., Grillier-Vuissoz, I., Kuntz, S., Mazerbourg, S., Husson, G., Myriam Vo, Flament, S., Martin, H., Chapleur, Y., Boisbrun, M., Optimization of troglitazone derivatives as potent anti-proliferative agents: Towards more active and less toxic compounds. Eur. J. Med. Chem., 2014, 83, 129-140
13. De Souza, R.M., Schapira, A., Safinamide for the treatment of Parkinson’s disease, Expert Opin. Pharmacotherapy, 2017, 18(9), 937-943.
14. Moya-García, A., Adeyelu, T., Kruger, F.A., Dawson, N.L., G. Lees, J.P., Overington, J.P., Orengo, C., Ranea, J.A.G. Structural and Functional View of Polypharmacology. Scientific Reports, 2017, 7, 10102.
15. Zhang, W., Bai, Y., Wang, Y., Xiao, W. Polypharmacology in Drug Discovery: A Review from Systems Pharmacology Perspective. Current Pharmaceutical Design, 2016, 22 (21), 3171-81.
16. Hopkins, A.L. Network pharmacology: the next paradigm in drug discovery. Nat. Chem. Biol , 2008, 4 (11), 682-690.