Polypharmacology: Drug Discovery for the Future

A Srinivas Reddy; Shuxing Zhang

Disclosures

Expert Rev Clin Pharmacol. 2013;6(1):41-47. 

In This Article

Abstract and Introduction

Abstract

In recent years, even with remarkable scientific advancements and a significant increase of global research and development spending, drugs are frequently withdrawn from markets. This is primarily due to their side effects or toxicities. Drug molecules often interact with multiple targets, coined as polypharmacology, and the unintended drug–target interactions could cause side effects. Polypharmacology remains one of the major challenges in drug development, and it opens novel avenues to rationally design the next generation of more effective, but less toxic, therapeutic agents. This review outlines the latest progress and challenges in polypharmacology studies.

Introduction

Drug discovery and development is a complex and expensive process.[1,2] Owing to the exponential growth of molecular data and fast advancement in technologies, the efforts of drug discovery have been tremendously amplified.[3–6] The philosophy of drug design has been transformed from 'one drug, one target' to 'one drug, multiple targets', coined as polypharmacology.[7–12] Polypharmacology is emerging as the next paradigm of drug discovery.[7,13–18] Polypharmacological phenomena include a single drug acting on multiple targets of a unique disease pathway or a single drug acting on multiple targets pertaining to multiple disease pathways. In addition, polypharmacology for complex diseases most likely uses multiple drugs acting on distinct targets, which are part of a network regulating various physiological responses.[7,19] The polypharmacological approaches aim to discover the unknown off-targets for the existing drugs (also known as drug repurposing).[15,20,21] The approach needs the systematic integration of the data derived from different disciplines including computational modeling, synthetic chemistry, in vitro/invivo pharmacological testing and clinical studies.[22,23]

Although not designed on purpose, numerous drugs are known for their multitargeting activities. One such example is aspirin, often used as an analgesic to relieve minor pains or as an antipyretic to reduce fever,[24] which also acts as an anti-inflammatory medication to treat rheumatoid arthritis,[25] pericarditis[26] and Kawasaki disease.[27] In addition, it has been used in the prevention of transient ischemic attacks,[28] strokes, heart attacks,[29] pregnancy loss[30] and even cancer.[31] Another example is sildenafil (Viagra®, Pfizer, NY, USA), which is a phosphodiesterase inhibitor. It was initially developed for hypertension and ischemic heart disease. However, it is now more frequently used to treat erectile dysfunction.[32] Certainly, kinase inhibitors are the elephant in the room regarding polypharmacology research. As a target class, kinases have received considerable attention over the last 20 years. There are currently 14 kinase inhibitors on the market for cancer treatment, with many more in clinical development.[33,34] Most of these cancer therapeutics inhibit more than one kinase, although they maintain reasonable selectivity over the serine/threonine and phosphoinositide-kinase classes.[34–38] On the other hand, polypharmacology can be considered a double-edged sword and cause clinical problems when it is not fully understood. Australia's Therapeutic Goods Administration (the Australian equivalent of the US FDA) cancelled the registration of lumiracoxib (a COX-2 selective inhibitor/nonsteroidal anti-inflammatory drug) in Australia owing to concerns that it may cause liver failure. Later, Merck voluntarily withdrew rofecoxib from the market because of the increased risk of heart attack and stroke associated with the long-term, high-dosage use. Staurosporine, a potent protein-kinase C inhibitor, is also known to interact with many other kinases (Figure 1) and is thus excluded from use in clinical practice.

Figure 1.

Staurosporine can interact with many targets as a potent pan-kinase inhibitor.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....