Polypharmacology: promises and new drugs in 2022

Abstract

Polypharmacology is an emerging strategy of design, synthesis, and clinical implementation of pharmaceutical agents that act on multiple targets simultaneously. It should not be mixed up with polytherapy, which is based on the use of multiple selective drugs and is considered a cornerstone of current clinical practice. However, this ‘classic’ approach, when facing urgent medical challenges, such as multifactorial diseases, increasing resistance to pharmacotherapy, and multimorbidity, seems to be insufficient. The ‘novel’ polypharmacology concept leads to a more predictable pharmacokinetic profile of multi-target-directed ligands (MTDLs), giving a chance to avoid drug-drug interactions and improve patient compliance due to the simplification of dosing regimens. Plenty of recently marketed drugs interact with multiple biological targets or disease pathways. Many offer a significant additional benefit compared to the standard treatment regimens. In this paper, we will briefly outline the genesis of polypharmacology and its differences to polytherapy. We will also present leading concepts for obtaining MTDLs. Subsequently, we will describe some successfully marketed drugs, the mechanisms of action of which are based on the interaction with multiple targets. To get an idea, of whether MTDLs are indeed important in contemporary pharmacology, we also carefully analyzed drugs approved in 2022 in Germany: 10 out of them were found multi-targeting, including 7 antitumor agents, 1 antidepressant, 1 hypnotic, and 1 drug indicated for eye disease.

Etrinabdione (VCE-004.8), a B55α activator, promotes angiogenesis and arteriogenesis in critical limb ischemia

“…In many cases, diseases with complex physiopathology are very difficult to be treated by monotargeted therapies, and usually requires concomitant therapies (polypharmacy) that have limitations such as therapy adherence and pharmacological interactions. In contrast, multipronged therapies (polypharmacology) may represent potential pharmacological therapies with better clinical benefits after providing a safe profile in humans and an appropriated target engagement as it is the case of reprofiling therapies with small molecules 50 .…”

Is Target-Based Drug Discovery Efficient? Discovery and “Off-Target” Mechanisms of All Drugs

“…It is well-established in pharmacology that the therapeutic effects of many drugs are mediated by a multitude of mechanisms (see Supporting Information 3). − Moreover, it was recently shown that “off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials”. − Having put all of these alongside the fact that even in target-based drug discovery, assessments of therapeutic effects play some role as terminal filters, it can be hypothesized that even for the “target-based” drugs, the therapeutic effects might not be entirely attributable to the scheme of target-based drug discovery. Therapeutic “off-target” mechanisms can be unconsciously and fortuitously selected by the phenotypic terminal filters.…”

Potentials and future perspectives of multi-target drugs in cancer treatment: the next generation anti-cancer agents

“…However, in theory, the number of useful combinations is unlimited if the molecular structure is properly selected and optimized. Also, in practice, it is most feasible to obtain ligands based on two to five pharmacophores [ 45 ]. Moreover, the drugs regimen of a combination therapy can indicate different absorption and distribution profiles which can affect the treatment outcomes.…”

“…In addition, it's generally easier to optimize the dose for a multi-targeted ligand than to do so separately for the components of the combination therapy regimen. Lastly, the clinical trial approval in a combination therapy requires each drug to be investigated separately, and then in combination with each other which is cost- and time-consuming while, MTDLs are time- & cost-efficient for clinical trials since a single compound is involved in the study [ 45 ].…”

“…The linking is the binding of two compounds that bind within their pharmacophores together through a linker (cleavable or not) to obtain a new compound capable of aiming multiple targets at the same time [ 58 , 59 ]. For example, trastuzumab emtansine, an FDA-approved drug [ 60 ], is an MTDL that linked an anti-HER2/neu antibody with emtansine (a microtubule inhibitor) through MCC (4-[N-maleimidomethyl]cyclohexane-1-carboxylate) linker [ 45 ]. Furthermore, the linking strategy also makes designing a variety range of hybridizations possible in comparison to the merge & fused strategies [ 61 ].…”