Polypharmacology: An underutilized paradigm in drug discovery

In the 1950s, Chemi Grünenthal marketed a small molecule drug to relieve symptoms of nausea and vomiting associated with morning sickness during pregnancy[1]. Hailed as a “wonder drug” for its powerful sedative properties, thalidomide was sold in 46 different countries, including Canada. Soon after thalidomide’s release, disturbing reports linked to the drug emerged from around the world. Studies confirmed that the wonder drug caused a litany of unfortunate adverse effects, the most severe being the malformation or absence of limbs (phocomelia) in newborns whose mothers had taken thalidomide during pregnancy1. The drug was removed from the market under pressure from the public in light of these findings, although it took over a year after warnings were issued for some markets to fully terminate sales[2]. It is estimated that thalidomide affected over 10,000 infants worldwide during its brief availability, though this likely underestimates the full impact of thalidomide given that stillbirths and miscarriages went not counted[3]. 

Despite its infamous past, thalidomide came back into use when Dr. Jacob Sheskin, a practicing physician in Jerusalem, prescribed the drug as a sedative to a leprosy patient[4]. Surprisingly, thalidomide cleared the painful inflammatory lesions under the skin caused by leprosy. Today, thalidomide is not only approved by the FDA for treatment of symptoms of leprosy, but has also gained significant attention as a chemotherapeutic against multiple myeloma and other cancers[1]. Thalidomide’s interaction with certain proteins in the body may cause adverse effects during pregnancy, but its interaction with other proteins simultaneously confers a therapeutic benefit in cancers. This realization that one drug may interact with several targets is what underlies the emergence of a new paradigm in drug discovery known as polypharmacology (Figure 1).

Figure 1. Thalidomide acts on several proteins through direct binding or on pathway. Relevant drug targets include NF-κB, Cereblon, VEGFR, and TNF-α.

Figure 1. Thalidomide acts on several proteins through direct binding or on pathway. Relevant drug targets include NF-κB, Cereblon, VEGFR, and TNF-α.

Medications have traditionally been designed with the aim of targeting a single protein with high specificity to avoid any unwanted effects arising from the same medication mistargeting another protein[5]. The concept that medications interact with multiple targets has long been viewed as undesirable as it is typically associated with adverse side-effects. The complexities of biology and pharmacology have, however, made such single-target, “magic bullet” drugs very rare. Instead, recent efforts have aimed to explore the possibility of exploiting polypharmacology to design more efficacious multitargeted drugs. 

Designing a multitargeted drug relies on elucidating the effects of drugs on a systemic level, by predicting which proteins the drug will likely bind and understanding the functional pathways that binding will perturb. Drugs capable of modulating multiple proteins within disease-relevant pathways are often more desirable than a compound that modulates a single target as they are predicted to have an additive or synergistic therapeutic effect[6].

A prime example of a disease that would benefit from polypharmacological techniques is cancer, where several aberrant proteins and pathways facilitate disease progression[6]. While some cancers may have a single protein driving malignancy and thus a highly specific drug may see initial success, redundancies and complexities in biological pathways often lead to compensation and resistance to targeted therapies. Combination chemotherapy, where multiple drugs are used to target multiple proteins, address this issue but have other drawbacks, such as non-uniform drug uptake into the diseased tissues, negative drug-drug interactions, and side-effects caused by each drug.

In contrast, a single multi-target drug would demonstrate consistent uptake while retaining the ability to modulate multiple proteins and pathways underlying certain cancers. An example of a cancer chemotherapeutic with such polypharmacological action is sunitinib[6]. Sunitinib targets multiple receptor tyrosine kinases (RTKs), a family of proteins that relay extracellular signals to actuate intracellular effector proteins and pathways. These pathways are often associated with increased cellular growth and proliferation, as well as aberrant cellular metabolism. When these RTKs are mutated, they often become permanently active, thereby leading to the uncontrolled proliferation that is characteristic of cancer. Sunitinib simultaneously inhibits several RTKs linked to cancer-promoting pathways, leading to enhanced efficacy compared with other treatment options. This multi-targeting nature led to its approval by the FDA in 2006 for both gastrointestinal stromal tumours and advanced kidney cancer, becoming the first drug to be approved for two separate indications simultaneously[7].

Figure 2.  The 2D/3D fused chemical representation of sunitinib. Receptor tyrosine-kinase ITK and VEGFR (red) with sunitinib (red) inhibiting the active site of each.

Figure 2.  The 2D/3D fused chemical representation of sunitinib. Receptor tyrosine-kinase ITK and VEGFR (red) with sunitinib (red) inhibiting the active site of each.

Polypharmacological approaches to drug discovery have faced many challenges arising from the complex nature of a biological system. Today, many of these challenges are being addressed with advancements in computer science, systems biology and bioinformatics. Cyclica is actively contributing to the advancement of polypharmacology as a paradigm for innovative and successful drug development by efficiently predicting the protein binders of drug candidates in silico. This information can be used to assess therapeutic potential, explain adverse effects, prioritize lead drug candidates, and explore drug repurposing opportunities. Awareness of polypharmacology in the early stages of drug development pipelines can optimize multitargeted drug discovery and lead to more effective medicines.

This blog was written by Tonny Huang, a graduate student at the Princess Margaret Cancer Center. Tonny has a deep interest in the applications of protein science for the betterment of human health. You can find him here on LinkedIn.


  1. Vargesson, N. Thalidomide-induced teratogenesis: History and mechanisms. Birth Defects Res C Embryo Today 105(2), 140-56 (2015).

  2. Webb, J. F. Canadian Thalidomide Experience. Canad Med Ass J 89, 987-92 (1963).

  3. Franks, M. E., Macpherson, G. R., Figg, W. D. Thalidomide. Lancet 363(9423), 1802-11 (2004).

  4. Rehman, W., Arfons, L. M., Lazarus, H. M. The Rise, Fall and Subsequent Triumph of Thalidomide: Lessons Learned in Drug Development. Ther Adv Hematol 2(5), 291-308 (2011).

  5. Rastelli, G., Pinzi, L. Computational polypharmacology comes of age. Front Pharmacol 6, 157 (2015).

  6. Anighoro, A., Bajorath, J, Rastelli, G. Polypharmacology: Challenges and Opportunities in Drug Discovery. J Med Chem 57, 7874-7887 (2014).

  7. U.S. Food & Drug Administration. (2006) FDA Approves New Treatment for Gastrointestinal and Kidney Cancer http://www.webwire.com/ViewPressRel.asp?aId=8446

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