Polypharmacology in Precision Oncology: Current Applications and Future Prospects

Abstract

Over the past decade, a more comprehensive, large-scale approach to studying cancer genetics and biology has revealed the challenges of tumor heterogeneity, adaption, evolution and drug resistance, while systems-based pharmacology and chemical biology strategies have uncovered a much more complex interaction between drugs and the human proteome than was previously anticipated. In this mini-review we assess the progress and potential of drug polypharmacology in biomarker-driven precision oncology. Polypharmacology not only provides great opportunities for drug repurposing to exploit off-target effects in a new single-target indication but through simultaneous blockade of multiple targets or pathways offers exciting opportunities to slow, overcome or even prevent inherent or adaptive drug resistance. We highlight the many challenges associated with exploiting known or desired polypharmacology in drug design and development, and assess computational and experimental methods to uncover unknown polypharmacology. A comprehensive understanding of the intricate links between polypharmacology, efficacy and safety is urgently needed if we are to tackle the enduring challenge of cancer drug resistance and to fully exploit polypharmacology for the ultimate benefit of cancer patients.

Anticancer Thiosemicarbazones: Chemical Properties, Interaction with Iron Metabolism, and Resistance Development

“…Given the complexity and heterogeneity of cancer, "dirty drugs" targeting multiple enzymes may avoid resistance mechanisms limiting the success of existing treatment schemes (48). Several chemotherapeutics have been shown to modulate more than a single molecular target or pathway, suggesting that such a promiscuous behavior may be key to long-term therapeutic efficiency (3,16). Also metalinteracting drugs, including thiosemicarbazones hit multiple targets related to tumor growth, drug resistance and metastasis ("triad of death", see 84 This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction.…”

Discovery of Novel Inhibitors Targeting Multi-UDP-hexose Pyrophosphorylases as Anticancer Agents

“…As for multi-target approaches (also known as polypharmacology), it is gaining attention in the field of drug discovery, especially for complex diseases like cancers because of significant advantages [48][49][50][51][52][53][54]. To begin with, if we can address multiple targets with just one drug, we will have less issues with pharmacokinetics and/or drug resistance.…”

The off-target kinase landscape of clinical PARP inhibitors

“…26 In addition, understanding of polypharmacology can lead to the exploitation of drugs in novel indications, such as the recent approval of crizotinib in ROS1-driven non small-cell lung cancer. [26][27][28] The selectivity and polypharmacology of PARP inhibitors within the PARP-family was recently characterised in vitro using an enzymatic inhibition assay. 29 Veliparib and niraparib were shown to be more selective for PARP1 and PARP2 compared to olaparib, rucaparib and talazoparib which show broader pan-PARP activity ( Figure 1b).…”

“…[17][18][19][20][21] Moreover, experimental and computational methods continue to uncover previously unknown off-targets of drugs. 19,[22][23][24][25] Alongside other factors such as pharmacokinetics, polypharmacology has been demonstrated to cause differences in side-effects between drugs of the same class. 26 In addition, understanding of polypharmacology can lead to the exploitation of drugs in novel indications, such as the recent approval of crizotinib in ROS1-driven non small-cell lung cancer.…”