When Single-Drug Magic Bullet Won’t Cut It - The transition from the single-target to the multi-target concept for drug design.

Single drug (the “Magic Bullet”) strategy is not adequate for treating chronic diseases.

Traditionally drugs have been designed with the aim of targeting a single biological entity “magic bullet”, usually a protein (the so-called “on-target”), with high selectivity to avoid any unwanted effects arising from mis-targeting other biological targets (“off-targets”).

On this basis, the concept of drugs interacting with multiple targets has long been flagged as undesirable, as it was inherently associated with adverse side effects. However, the complexity of the chronic illnesses, such as cancer, immune disorders, mental illnesses and cardiovascular diseases has clearly demonstrated that such single-target drugs are inadequate to achieve a therapeutic effect.

Diseases of infection, of neurodegeneration (such as Alzheimer’s and Parkinson’s diseases), and of malignancy (cancers) have complex and varied causative factors where cures or at least treatments are sought are complex ones involving many potential defects in the structure, function, or regulation of the cells involved.

In parallel, we have learned that molecules hitting more than one target may possess in principle a safer profile compared to single-targeted ones.  Thus, there is a need for a “multi-component/multi-target” approach involving control over a number of target sites to develop more effective therapies targeting resistant and complex diseases.

The drug discovery community both in academia and biotech/pharmaceutical companies points out to such need in that a plethora of “multi-component/multi-target” drugs are already available on the market. As a clear proof of such translational success of multi- target drugs into the clinic, an analysis performed within the US Food and Drug Administration (FDA)- approved new molecular entities (NMEs) from 2015 to 2017 (status September 2017), biotech drugs (large molecules--proteins, peptides and monoclonal antibodies) represent 31% of the novel NMEs, nearly approaching the number of single-target small molecule drugs (34%) which build on the premise of a personalized treatment. Although the number of single-target small molecules (34%) is still greater than that of multi-target drugs (21%), the latter keeps increasing compared to previous years (16%). However, if we broaden our view and reason in terms of general polypharmacology, we can add together the 21% of multi-target drugs and the newly approved therapeutic combinations (10%). In this way, the total percentage of multi-component/multi-target (31%) drugs approaches that of single-target small molecule drugs (34%), supporting the attractiveness of polypharmacological strategies, especially in certain therapeutic areas, such as anti-infective, nervous system, and anti- neoplastic agents.

Our Solution

Multi-Target Manifest Opportunities.

In the near future, we expect researchers to design multi-component/multi-target compounds with a specific and well-defined polypharmacological mechanism of action, utilizing computational studies or simply using rational observations to provide a solution to the current productivity crisis facing the scientific community engaged in drug discovery and development.

For multi-component/multi-target therapies, small compounds are intrinsically more suitable than larger molecules. Polypharmacology approaches are not well resourced, particularly in the early stages of drug discovery.

We at Innox emphasize on clinically and biologically validated disease targets, and design “smart” drug candidates with one or more compounds or fragments already confirmed association with those targets increasing our chances of success in the experimental testing both in vitro and in vivo, thus, increasing the success of drug design for complex diseases, and therefore reduces the cost and duration of development compared to conventional synthetic and biologic drug development methods.

Our source of compounds or molecules are plants which have a wide range of diversity of multi-dimensional chemical structures with biological function modifying abilities.  Among anticancer drugs approved in the time frame of about 1940–2002, approximately 54% were derived from plants.

Their efficacy is related to the complexity of their well-organized three-dimensional chemical and steric properties, which offer many advantages in terms of efficiency and selectivity of molecular targets. As a successful example of drug development from plants, artemisinin and its analogs are presently in wide use for the anti-malaria treatment. In the case of antihypertensives, where about 64% of newly-synthesized drugs have their origins in plants.

Another advantage Innox is aiming to capitalize in terms of drug development is the “synergism” of designing multiple compounds or molecules in one drug; that is, often multiple components play a synergistic role which is greater than that of the individual drug as the “1 disease, 1 target, 1 drug” mode cannot treat some complex diseases effectively, such as cancer, neurodegenerative diseases, cardiovascular disease and diabetes.

Thus, we at Innox shift the treatment to the “multi-component and multi-targets” mode for combination therapies.

Our Focus

Cancer and neurodegenerative diseases represent one of the most chronic physiological ailments.  Studies show that these diseases are associated with multiple signaling pathways that regulate cell death and survival and have been well investigated in tumorigenesis, including DNA damage, cell cycle aberrations, inflammation, immunity, and oxidative stress. These pathways are in the center of our drug development program. 

Cancer and neurodegenerative diseases represent one of the most chronic physiological ailments. Aging, characterized by the deterioration of physiological functions necessary for survival and fertility, is considered as a major risk factor for the these disorders.

Cancer has been associated with generalized hallmarks such as sustenance of proliferative signaling, evasion of growth suppressors, resistance to cell death, acquisition of replicative immortality, induction of angiogenesis, and activation of invasion and metastasis. Interestingly, current research has indicated parameters such as deregulated cellular energetics and avoidance of immune destruction, as pertinent hallmarks. These features are effectuated by genome instability, mutations and/ or tumor-promoting inflammation.

Neurodegeneration is characterized by dysfunction and loss of neurons, impairment of synaptic plasticity, proteinopathies, which include misfolded amyloid-β (Aβ) and tau in Alzheimer’s disease (AD), α-synuclein in Parkinson’s disease (PD).

There is a significant overlap between the genes upregulated in the neurodegenerative diseases and downregulated in cancer, and between the genes downregulated in the neurodegenerative diseases and upregulated in cancer.

Multiple signaling pathways that regulate cell death and survival have been well investigated in tumorigenesis, including DNA damage, cell cycle aberrations, inflammation, immunity, and oxidative stress; these pathways have now been shown to be associated with neurodegenerative diseases as well.  

Significant knowledge has been generated on the shared or distinct roles of overlapping molecules that have been significantly correlated with the pathophysiology of both cancer and neurodegenerative diseases, such as p53, cyclin D, cyclin E, cyclin F, and protein phosphatase 2A (PP2A).

Studying these signaling pathways and hyperinflammation, it is a natural progression for Innox to focus on drug development targeting cancer and neurodegenerative diseases.  Specifically, our emphasis is on halting, preventing or slowing down the pro-inflammatory cycle to stop the disease progression.