Viewpoint Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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Harnessing Polypharmacology with Medicinal Chemistry Maria Laura Bolognesi* Department of Pharmacy and Biotechnology, Alma Mater Studiorum − University of Bologna, I-40126 Bologna, Italy
ACS Med. Chem. Lett. Downloaded from pubs.acs.org by 193.93.192.35 on 02/15/19. For personal use only.
ABSTRACT: Polypharmacology has expanded enormously over the last ten years, with several multitarget drugs (MTDs) already in the market. This Viewpoint provides a basis for a discussion about the critical need to develop MTDs in a more rationale and conscious way. A checklist to maximize success in polypharmacology is proposed.
KEYWORDS: Multitarget drugs, medicinal chemistry, polypharmacology, multitarget drug discovery, checklist
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Medicinal Chemistry.5 About 10 years later, with 776 citations (Google Scholar, January 2019), the response to this publication has been very positive. Apart from personal experience, the increasing and substantial rate at which interest in polypharmacology approaches is growing is there for all to see. Particularly, we considered two performance indicators that refer to early and late stages of the pipeline: the number of publications and the number of Food and Drug Administration (FDA)-approved New Molecular Entities (NME) with a polypharmacological profile. A Journal of Medicinal Chemistry Web site search (January 2019) for the articles containing the keyword “multitarget” (and/or “multi-target”) retrieved 265 entries. Remarkably, 233 (88%) of these publications have been issued in the last 10 years (Figure 1). An analogous search in ACS Medicinal Chemistry Letters gave a similar trend. For the late pipeline stage, we updated an analysis6 of the single-target, MTDs (according to number of targets in DrugBank) and combinations among the FDA-approved NMEs from 2015 to 2018. Although the total number of single-target small molecules (55%) is still greater than that of MTDs (32%) in the selected time frame, this value is higher than
ecent research into ground-breaking network pharmacology1 has significantly shifted the drug discovery paradigm for many multifactorial disease categories, spanning over nearly every therapeutic area. From the integration of medicine with network science, disease is seen as a result of the systemic breakdown of physiological networks. Thus, the goal of therapy is to restore the perturbed network by simultaneously targeting drugs to key components and checkpoints. Given that robust homeostasis and redundant mechanisms are typical of biological network systems, it is intuitive that single-target drugs are often inadequate and fraught with adverse side-effects. Conversely, the simultaneous modulation of several targets through a wellconcerted pharmacological approach is essential to achieve the desired therapeutic effect. In 2006, Hopkins and colleagues2 proposed this approach as “polypharmacology”. The definition of polypharmacology was first introduced to the National Library of Medicine (NLM) curated vocabulary in 2014 as “the design or use of pharmaceutical agents that act on multiple targets or disease pathways”. Hence, polypharmacology encompasses two different scenarios: multiple drugs binding to different targets, and a single drug binding to multiple targets within a given network. Combining multiple drugs in a combination therapy regimen is a well-established approach for many diseases but with potential drug−drug interaction risk. Recently, the development of single-molecule multitarget drugs (MTDs) has become an increasingly feasible and attractive polypharmacology option for both academic and industrial medicinal chemists.3 The discovery of an innovative, first-inclass MTD has the potential to offer patients significant benefits, as well as adding substantially to the developer’s bottom-line as these medicines might become the standard of care in a near future. Attracted by the potential of polypharmacology and used to the multifaceted profile of polyamines, in the late 1990s, we at the Alma Mater Studiorum − University of Bologna embarked on a drug discovery project to develop multitarget-directed ligands (MTDLs) against Alzheimer’s disease.4 In 2008, our interpretive account on the field was published in the Journal of © XXXX American Chemical Society
Figure 1. Number of “multitarget” articles per year extracted from the J. Med. Chem. Web site.
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DOI: 10.1021/acsmedchemlett.9b00039 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
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of MTDL and the features that provide a clear competitive advantage with respect to single-target drugs. • Target identification − a new MTDL should be directed to networked targets whose connectivity has been proven. This can be done by using system biology and polypharmacological modeling but also by exploiting the huge opportunity of the big data era.11 • Pharmacokinetic − The physicochemical properties of MTDLs have been found to be less druglike than singletarget ones.12 Early ADME studies should be included in the initial profiling. • Activity in primary assays − A fundamental prerequisite is that activities against the targets of interest (isolated proteins) are balanced. Ideally, potencies should differ by no more than 1 order of magnitude. • Selectivity − Hits should be tested for activity against biological target isoforms and closely related proteins to demonstrate the intended selective nonselectivity.7 • Activity in cellular assays − Activity in these assays should be viewed as the early proof of concept. Different from isolated protein assays, cell-based screening systems maintain molecular−pathway interactions. A superior activity with respect to single-target reference compounds used alone and in combination is required. The points delineated above may sound trivial to those who are experienced in the field but hopefully useful to the rising community of the newcomers. My wish is that they are a first step toward the introduction of a checklist in the field of polypharmacology. In aviation and medicine, the use of checklists has dramatically raised effectiveness and reduced errors. A similarly high-risk endeavor like multitarget drug discovery (MTDD) would also benefit by the use of a checklist. It can provide clear initial goals and a framework for go/no-go decision making along the pipeline. It would be valuable also for consideration by funding agencies and scientific journals dealing with these topics. Academic and industrial scientists working in the field since its inception have learned from one another, appreciated progress and obstacles in different aspects of MTDD, and realized collaboration is essential. Hopefully, the checklist might be developed and implemented by including the suggestions coming from across the multidisciplinary community. A network is an intrinsically open, cooperative, and all-inclusive concept. MTDD involves many disciplines and demands strong expertise in each field. If we want to face and overcome the problems identified above, once more, the network concept is the key!
that found in the previous analysis (31%). Interestingly, the number of combinations has slightly decreased (from 15% to 13%). “It was the best of times, it was the worst of times.” are the opening lines of Dickens’ famous novel, A Tale of Two Cities. The same can be said for polypharmacology. The case for believing that we live in the golden age is strengthened by the data presented above. However, we cannot ignore critical points worthy of serious attention: (i) many of the reported endeavors are clustered around a few therapeutic areas, while overlooking very promising ones such as cardiovascular and metabolic diseases; (ii) too many newly reported MTDLs are “follow-on” compounds, with high chemical structure similarity and directed to the same target combinations, without adding therapeutic value; (iii) we have been over-reliant on the hybrid drug design approach, sometimes ignoring that framework combination often results in large, dual ligands; (iv) fragment-based approaches are still underexplored, despite the innate tendency of fragments to bind several targets; (v) drug repurposing, although in principle very productive in terms of saving costs and time, might diminish the incentives for innovation in pioneering new drugs; and, finally, (vi) in some publications (fortunately few in number) it seems as if the word “multi-target” is used as a neologism to attract attention. In my opinion, the much-anticipated evolution of polypharmacology from a promising paradigm to the drug discovery for the future should pass through a semantic change. Today still the words “promiscuous” and “multi-target” are used somewhat interchangeably. However, drug promiscuity refers not only to the interaction with the desired targets but also to off-target interactions with the risk of side effects. Promiscuous compounds are those that show activity either with many similar proteins with different physiological roles or in multiple application trials because of misleading assay interpretation. Hits with these structural liabilities tend to make very poor drugs and should be discarded as early as possible. Hence, “promiscuous” should have an intrinsic negative connotation in this context. Conversely, as highlighted by the pioneer Richard Morphy, MTDs are small molecules rationally designed to show a selective nonselectivity.7 In other words, being directed to the disease-relevant target network and able to produce the optimal network perturbations, they have a high likelihood of eliciting the desired therapeutic response and limiting adverse effects. I would stress that the changing of definitions should be undertaken not only for reasons of clarification but also to strengthen the concept that has the potential to be one of the most fascinating possibilities to provide a cure for currently incurable complex diseases. How to transform the challenge of drug promiscuity into the opportunity of multitarget drugs?8 “Chance favors only the prepared mind,” said Louis Pasteur. We are confident that medicinal chemistry, which, via the trained and specialized mind has produced, since 1935, more potent and more useful drugs,9 can rise to the occasion. More sophisticated strategies and technologies to access MTDLs have expanded the available toolbox.10 In parallel, it would be extremely useful to develop a common framework to help the community at critical stages (e.g., to select compounds to be progressed for further development and to set milestones for project advancement). Without being exhaustive and on the basis of current practice, I point to the following desired features and studies that must be completed to demonstrate the efficacy
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Maria Laura Bolognesi: 0000-0002-1289-5361 Notes
The author declares no competing financial interest.
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ACKNOWLEDGMENTS I am grateful to Michele Rossi and Elisa Uliassi for providing data and helping to compile data, and to Rona R. Ramsay for critical reading of the manuscript. COST Action CA15135 “Multi-target paradigm for innovative ligand identification in the drug discovery process (MuTaLig)” is kindly acknowledged for the support in networking and mutual cooperation in the field. B
DOI: 10.1021/acsmedchemlett.9b00039 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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ABBREVIATIONS FDA, Food and Drug Administration; MTDLs, multitargetdirected ligands; MTD, multitarget drug; MTDD, multitarget drug discovery; NLM, National Library of Medicine; NME, new molecular entity
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REFERENCES
(1) Hopkins, A. L. Network pharmacology: the next paradigm in drug discovery. Nat. Chem. Biol. 2008, 4, 682−690. (2) Hopkins, A. L.; Mason, J. S.; Overington, J. P. Can we rationally design promiscuous drugs? Curr. Opin. Struct. Biol. 2006, 16, 127−136. (3) Bolognesi, M. L. Polypharmacology in a single drug: multitarget drugs. Curr. Med. Chem. 2013, 20, 1639−1645. (4) Melchiorre, C.; Andrisano, V.; Bolognesi, M. L.; Budriesi, R.; Cavalli, A.; Cavrini, V.; Rosini, M.; Tumiatti, V.; Recanatini, M. Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer’s disease. J. Med. Chem. 1998, 41, 4186−4189. (5) Cavalli, A.; Bolognesi, M. L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem. 2008, 51, 347−372. (6) Ramsay, R. R.; Popovic-Nikolic, M. R.; Nikolic, K.; Uliassi, E.; Bolognesi, M. L. A perspective on multi-target drug discovery and design for complex diseases. Clin. Transl. Med. 2018, 7, 3. (7) Morphy, R. Selectively nonselective kinase inhibition: striking the right balance. J. Med. Chem. 2010, 53 (4), 1413−1437. (8) Anighoro, A.; Bajorath, J.; Rastelli, G. Polypharmacology: challenges and opportunities in drug discovery. J. Med. Chem. 2014, 57, 7874−7487. (9) Burger, A. Molecular Modification in Drug Design. J. Med. Chem. 1965, 8, 277−277. (10) Proschak, E.; Stark, H.; Merk, D. Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds. J. Med. Chem. 2019, 62, 420−444. (11) Hu, Y.; Bajorath, J. Entering the ’big data’ era in medicinal chemistry: molecular promiscuity analysis revisited. Future Sci. OA 2017, 3, FSO179. (12) Morphy, R.; Rankovic, Z. The physicochemical challenges of designing multiple ligands. J. Med. Chem. 2006, 49 (16), 4961−70.
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DOI: 10.1021/acsmedchemlett.9b00039 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
