Systems Pharmacology


Continued from page 41


28 Bennett, DA. Yu, L and De Jager, PL. Building a Pipeline to Discover and Validate Novel Therapeutic Targets and Lead Compounds for Alzheimer’s Disease. Biochem. Pharmacol. 88, 617-630 (2014). 29 Christensen, CM, Grossman, MD and& Hwang, J. The Innovator’s Prescription: A Disruptive Solution for Health Care. McGraw-Hill, New York, NY, USA. (2009). 30 US National Research Council. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease. US National Academies Press, Washington DC USA (2011). http://www.nap.edu/catalog/13 284/toward-precision- medicine-building-a- knowledge-network-for- biomedical-research. 31 GenomeWeb. Personalized Medicine 2018: More Drugs, Greater NGS Adoption, Growing Appreciation of Dx Value. December 26th, 2018. https://www.genomeweb.com/ molecular- diagnostics/personalized- medicine-2018-more-drugs- greater-ngs-adoption- growing#.XC1VA_x7nEY. 32 Dai, S-X et al. Proteome- Wide Prediction of Targets for Aspirin: New Insight into the Molecular Mechanism of Aspirin. PeerJ 4:e1791 (2016). https://doi.org/10.7717/ peerj.1791. 33 Anighoro, A, Bajorath, J and Rastelli, G. Polypharmacology: Challenges and Opportunities in Drug Discovery. J. Med. Chem. 57, 7874-7887 (2014). 34 Talevi, A. Multiple-Target Pharmacology: Possibilities and Limitations of the “Skeleton Key Approach” from a Medicinal Chemist Perspective. Front. Pharmacol. 22nd September (2015). https://doi. org/10.3389/fphar.2015.00205.


The systems pharmacology drugs approved by


the FDA between 2015-17 were predominantly anti-neoplastic agents constituting 12 of the 21 (57%) approved NMEs. An additional four approved systems pharmacology drugs were thera- pies for CNS indications, with the remaining five drugs approved for anti-infective, musculoskeletal, genitourinary and alimentary tract /metabolism disorders35. Systems pharmacology drugs are most relevant for disease states involving large target networks and pathways, as is the case with most cancers. Cancer cells are characterised by a trans- formed phenotype associated with uncontrolled proliferation and immortality. This abnormal cell activity is sustained by significant protein deregu- lation. For example, the protein kinase family con- sists of more than 500 different proteins and they are involved in multiple cellular pathways and net- works. The original one drug-one target model produced highly-selective kinase inhibitors. However, it has become increasingly clear that more effective targeted therapies based on kinase inhibitors should target the disease at multiple tar- get nodes in the network, which explains the sig- nificant efforts to create systems pharmacology- based kinase inhibitors in the treatment of several forms of cancer. A representative sample of FDA approved marketed systems pharmacology drugs in oncology are shown in Table 2. We concur with Talevi that there are three more


general applications where systems pharmacology drugs can be expected to impact in the future. Firstly, and as noted above, complex disease condi- tions such as cancer and CNS disease are a clear focus of current effort and development (Table 2). Another area of applicability is in drug resistance. The ability to simultaneously modulate different targets could be advantageous to individuals expressing intrinsic or induced variability in drug response due to modifications in key disease-rele- vant biological pathways and activation of com- pensatory mechanisms34. Apart from the obvious applications in the field of antimicrobial chemotherapy (it is less probable to develop resis- tance linked to single-point mutations against multi-target than single-target agents) this strategy could also be pertinent to treat non-infectious con- ditions characterised by high incidence of the drug resistance phenomena, eg epilepsy. One final appli- cation for consideration is in prospective Drug Repositioning. We have previously highlighted the resurgence of Drug Repurposing


and Continued on page 43 42


Repositioning (DRPx)1. However, most such cases have occurred by serendipity or exploitation of the original mechanism of action, using a retrospective


DRPx approach. Talevi has argued that in contrast prospective DRPx should explore drug-reposition- ing possibilities much earlier in the drug discovery process. This would entail the design of multi-pur- pose drugs to treat different indications; such as co-morbidity disorders (eg diabetes and cardiac disease).


Conclusions The reality of


the one drug-multi-target-


pathway/network systems pharmacology drug appears to afford considerable advantages over the one drug-one target or combination drug-multi tar- get approaches. However, the tremendous thera- peutic potential of multi-target drugs, their ratio- nal discovery and their development still represent a formidable challenge. In addition the necessity of balancing the beneficial polypharmacology versus the harmful promiscuity of such drugs still needs to be evaluated as more of these drugs are brought to market. Nonetheless, building on the accumulated evidence, the concept of systems pharmacology drugs has made rapid and spectacular progress from being an emerging paradigm when first enun- ciated at the beginning of 2000 to one of the hottest topics in drug discovery and development in 2017-18. Does the merging of systems biology, precision medicine, precision medicine drugs and now systems pharmacology drugs provide the harbinger of more safe and efficacious drugs? Initial indications appear to suggest that there is indeed a new dawn breaking for patients and the products they rely on to keep them healthy and alive.


DDW


Dr Kirkwood A. Pritchard Jr is a Co-Founder, CSO and Board Director of ReNeuroGen LLC, a virtual pharmaceutical company developing sys- tems pharmacology therapies for the treatment of neurological diseases. He is also a Co-Founder and Board Director of HDL-Dx, a diagnostics compa- ny developing an assay to determine functionality of HDL. In addition, he is a tenured Research Professor in the Division of Pediatric Surgery, Department of Surgery, at the Medical College of Wisconsin (Milwaukee, Wisconsin, USA). He has broad and diverse translational research interests in a number of disease indications including stroke, multiple sclerosis, traumatic brain injury, sickle cell disease and bronchopulmonary dysplasia in pre- mature babies. He holds a PhD from Ohio State University (Columbus, Ohio, USA) and undertook a postdoctoral fellowship at Albert Einstein College of Medicine (New York, NY, USA).


Drug Discovery World Winter 2018/19


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