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It necessitates not only the share of expertise, equipment and facilities but also the share of the financial burden towards the common goal of bringing a drug to the market. Furthermore, it is essential to bridge the gap between early stage drug discovery and the industry with specialized organization that dedicates their work in generating the necessary additional value to any drug or technological innovation. These organizations are particularly crucial to ensure the commercial development of anticancer drugs as it is a very costly endeavor. However, an important shift in philosophy occurred in academia that is now focused, not only on basic research, but also in the development of new therapies usually in collaboration with the pharmaceutical industry.

We have seen that the integration of academic and industrial research presents challenges but still leads to great benefit to both research centers and ultimately to society. The recruitment of a pool of competent multidisciplinary scientists who will work in cooperation, not in isolation is a key step to efficiently utilize academic research efforts in cancer drug discovery. Early target identification and proper hit selection are crucial for success and, if necessary it can be performed using services provided by organizations able to perform high throughput screening.

Another key condition promoting academic-industrial cooperation would be the accessibility to hospital cancer units facilitating translational research activities. Also, essential is the creation of strategies for graduate student integration within the academic drug discovery program keeping in mind their success and confidentiality requirements. Last but not least, adequate financial support from a combination of public, private and industrial partners is of vital importance.

On this point, it would be important to reform the grant application system by direct allocation of public funds to academic institutions in proportion to its size who will be responsible for its fair distribution within its walls. The objective of the institutions would be to support early career researchers giving them a chance to rapidly launch their independent research for at least five years. Thereafter, the institution would be responsible to maintain, diminish or withdraw support based on their accomplishments. It is understood that, at the beginning of the new system, the institution would support already established and successful researchers.

Additional private and industrial funding opportunities would still be available to universities based on classic grant applications system.

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In recent years, an important shift in philosophy allows a blend of curiosity-driven and market-driven research activities within academic centers. This new thinking promotes active cooperation among all partners academic, industrial and medical researchers as well as various sponsors and community representatives involved in cancer drug discovery activities.

We also see the creation of organizations that generate additional value around a technology and facilitate its commercialization. They provide indispensable support to further advance early drug discovery towards a strong partnership with pharmaceutical industry. This type of business could very well be the catalyst needed to promote and stimulate academic-pharmaceutical interactions. If not already available, it is a corporate model that can easily be established elsewhere.

Drug discovery

Globally, this would accelerate drug discovery processes and outcomes for the benefit of humankind. The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Skip to Main Content. Search in: This Journal Anywhere. Advanced search. Submit an article Journal homepage. Berube uqtr. Pages Received 21 Sep In this article Close 1. Introduction 2. Cancer drug discovery: academic and industrial research 3. Conclusion 4.

Expert opinion References. How to utilize academic research efforts in cancer drug discovery. Introduction The development of a new medicine requires tremendous investments not only in research time but also in financial resources. Cancer drug discovery: academic and industrial research An excellent review regarding academic drug discovery was recently written by Everett [ 1 Everett JR. Conclusion Today, bearing in mind the huge cost of cancer research programs much attention is given to improve the link between academic and pharmaceutical drug discovery laboratories.

Declaration of interest The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. Reviewer disclosures Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Everett JR. Additional information Funding This paper was not funded. The definition of "target" itself is something argued within the pharmaceutical industry. Generally, the "target" is the naturally existing cellular or molecular structure involved in the pathology of interest that the drug-in-development is meant to act on. However, the distinction between a "new" and "established" target can be made without a full understanding of just what a "target" is.

This distinction is typically made by pharmaceutical companies engaged in discovery and development of therapeutics.

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In an estimate from , human genome products were identified as therapeutic drug targets of FDA-approved drugs. This does not imply that the mechanism of action of drugs that are thought to act through a particular established target is fully understood. In general, "new targets" are all those targets that are not "established targets" but which have been or are the subject of drug discovery campaigns. These typically include newly discovered proteins , or proteins whose function has now become clear as a result of basic scientific research.

The majority of targets currently selected for drug discovery efforts are proteins. The process of finding a new drug against a chosen target for a particular disease usually involves high-throughput screening HTS , wherein large libraries of chemicals are tested for their ability to modify the target.

For example, if the target is a novel GPCR , compounds will be screened for their ability to inhibit or stimulate that receptor see antagonist and agonist : if the target is a protein kinase , the chemicals will be tested for their ability to inhibit that kinase. Another important function of HTS is to show how selective the compounds are for the chosen target, as one wants to find a molecule which will interfere with only the chosen target, but not other, related targets. It is very unlikely that a perfect drug candidate will emerge from these early screening runs.

One of the first steps is to screen for compounds that are unlikely to be developed into drugs; for example compounds that are hits in almost every assay, classified by medicinal chemists as " pan-assay interference compounds ", are removed at this stage, if they were not already removed from the chemical library.

At this point, medicinal chemists will attempt to use structure-activity relationships SAR to improve certain features of the lead compound :. This process will require several iterative screening runs, during which, it is hoped, the properties of the new molecular entities will improve, and allow the favoured compounds to go forward to in vitro and in vivo testing for activity in the disease model of choice.

Amongst the physico-chemical properties associated with drug absorption include ionization pKa , and solubility; permeability can be determined by PAMPA and Caco PAMPA is attractive as an early screen due to the low consumption of drug and the low cost compared to tests such as Caco-2, gastrointestinal tract GIT and Blood—brain barrier BBB with which there is a high correlation. A range of parameters can be used to assess the quality of a compound, or a series of compounds, as proposed in the Lipinski's Rule of Five.

Such parameters include calculated properties such as cLogP to estimate lipophilicity, molecular weight , polar surface area and measured properties, such as potency, in-vitro measurement of enzymatic clearance etc. Some descriptors such as ligand efficiency [17] LE and lipophilic efficiency [18] [19] LiPE combine such parameters to assess druglikeness. While HTS is a commonly used method for novel drug discovery, it is not the only method.

It is often possible to start from a molecule which already has some of the desired properties. Such a molecule might be extracted from a natural product or even be a drug on the market which could be improved upon so-called "me too" drugs. Other methods, such as virtual high throughput screening , where screening is done using computer-generated models and attempting to "dock" virtual libraries to a target, are also often used. Another important method for drug discovery is de novo drug design , in which a prediction is made of the sorts of chemicals that might e.

For example, virtual screening and computer-aided drug design are often used to identify new chemical moieties that may interact with a target protein. There is also a paradigm shift in the drug discovery community to shift away from HTS, which is expensive and may only cover limited chemical space , to the screening of smaller libraries maximum a few thousand compounds. These include fragment-based lead discovery FBDD [26] [27] [28] [29] and protein-directed dynamic combinatorial chemistry.

Further modifications through organic synthesis into lead compounds are often required. Such modifications are often guided by protein X-ray crystallography of the protein-fragment complex. Phenotypic screens have also provided new chemical starting points in drug discovery.

These screens are designed to find compounds which reverse a disease phenotype such as death, protein aggregation, mutant protein expression, or cell proliferation as examples in a more holistic cell model or organism. Smaller screening sets are often used for these screens, especially when the models are expensive or time-consuming to run.

Once a lead compound series has been established with sufficient target potency and selectivity and favourable drug-like properties, one or two compounds will then be proposed for drug development. The best of these is generally called the lead compound , while the other will be designated as the "backup".

Traditionally many drugs and other chemicals with biological activity have been discovered by studying allelopathy — chemicals that organisms create that affect the activity of other organisms in the fight for survival. Despite the rise of combinatorial chemistry as an integral part of lead discovery process, natural products still play a major role as starting material for drug discovery. For certain therapy areas, such as antimicrobials, antineoplastics, antihypertensive and anti-inflammatory drugs, the numbers were higher. Natural products may be useful as a source of novel chemical structures for modern techniques of development of antibacterial therapies.

Despite the implied potential, only a fraction of Earth's living species has been tested for bioactivity. Many secondary metabolites produced by plants have potential therapeutic medicinal properties. These secondary metabolites contain bind to and modify the function of proteins receptors, enzymes, etc. Consequently, plant derived natural products have often been used as the starting point for drug discovery. Until the Renaissance , the vast majority of drugs in Western medicine were plant -derived extracts. Jasmonates are important in responses to injury and intracellular signals.

They induce apoptosis [53] [54] and protein cascade via proteinase inhibitor, [53] have defense functions, [55] and regulate plant responses to different biotic and abiotic stresses. Jasmonate derivatives JAD are also important in wound response and tissue regeneration in plant cells. They have also been identified to have anti-aging effects on human epidermal layer. Salicylic acid SA , a phytohormone , was initially derived from willow bark and has since been identified in many species.

It is an important player in plant immunity , although its role is still not fully understood by scientists. They have salicylic acid binding proteins SABPs that have shown to affect multiple animal tissues. They also play an active role in the suppression of cell proliferation. Microbes compete for living space and nutrients. To survive in these conditions, many microbes have developed abilities to prevent competing species from proliferating. Microbes are the main source of antimicrobial drugs.

Streptomyces isolates have been such a valuable source of antibiotics, that they have been called medicinal molds. The classic example of an antibiotic discovered as a defense mechanism against another microbe is penicillin in bacterial cultures contaminated by Penicillium fungi in Marine environments are potential sources for new bioactive agents. It took until when the first marine-derived drug was approved. Several other marine-derived agents are now in clinical trials for indications such as cancer, anti-inflammatory use and pain.

One class of these agents are bryostatin -like compounds, under investigation as anti-cancer therapy. Nitrogen-based heterocycles are of particular importance in anti-cancer drug design, featuring in almost three-quarters of the heterocyclic anticancer agents approved by the FDA between and Of all the nitrogen heterocycles, indoles are among the most valuable, with research having demonstrated their ability to induce cell death in a number of cancer cell lines 2.

Over the last few decades, indole and its derivatives have been shown to modulate a number of biological pathways implicated in the progression of cancer.

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These include the prevention of cell signalling, normal cell cycle progression, tumour vascularisation and DNA repair, as well as the ability to induce cellular oxidative stress and cell death. Two of the most important early indole-based anticancer agents are vincristine and vinblastine — recognised for their tubulin polymerisation inhibition since the early-mid s, and both still of clinical importance today.

The inhibition of tubulin polymerisation is the mechanism of action of vinblastine, which leads to cell cycle arrest, halting cancer cell division 3. Indolocarbazoles are a closely-related derivative of indoles which, much like with the wider remit of heterocycles themselves, exhibit a broad range of activities, and have therefore received significant focus in recent years for their anti-cancer potential. Of particular significance is the proficiency of many indolocarbazoles as protein kinase inhibitors, where constitutively active protein kinases are often key factors in the malignant transformation of cells during cancer initiation.

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One such indolocarbazole, the anti-cancer agent midostaurin an indolocarbazole-based multi-target protein kinase inhibitor , has been approved by the FDA for the treatment of acute myeloid leukaemia as recently as April , which demonstrates just how relevant nitrogen-based heterocycles are for anti-cancer drug design, even to this day. Oxygen-containing heterocycles also feature prominently in many anti-cancer drugs. Among the earliest to be discovered, paclitaxel is a key drug in cancer therapy. Containing an oxetane ring, its mode of action is based on the depolymerisation of microtubule polymers, resulting in progression inhibition of mitosis in cancer cells.

Similar to the mode of action taken by vinblastine, this results in the retardation of cancer cell division, ultimately halting cancer in its tracks. Despite its benefits, however, there are a number of systemic sideeffects that have been correlated to the drug, including hypersensitivity, hematological issues and neurotoxicity. As a result, much effort has been devoted to finding alternative therapies that have fewer adverse effects, but still demonstrate the strong therapeutic potential of paclitaxel.

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More recently-developed oxygen-containing heterocyclic anti-cancer drugs include microtubule inhibitors cabazitaxel and eribulin, used to treat prostate and metastatic breast cancer respectively. Cabazitaxel Figure 2 is a tubulin-stabiliser, but is thought to be of particular interest for the treatment of multidrug-resistant tumours owing to its resistance to cellular efflux by the p-glycoprotein efflux pump, expressed by a number of resistance cancer cells 4,5.

Cabazitaxel is also able to cross the blood-brain barrier.

Drug discovery and development process

As mentioned, eribulin is used to treat advanced breast cancer, and is not only effective but exhibits a low level of toxicity compared to alternative cytotoxic agents, making it ideal for patients 7. In addition to this, recent research has led to the repurposing of existing oxygen-based heterocyclic drugs originally developed for other disease areas, for use as anti-cancer agents.

One notable example is auranofin, a gold-containing heterocyclic compound used historically for the treatment of rheumatic arthritis. Numerous studies are being undertaken to assess auranofin as a therapeutic agent for the treatment of many cancer types, including leukaemia, lymphoma and ovarian cancer where it recently received FDA approval to undergo Phase II clinical trials. Repurposing drugs in this way is a far more affordable approach to drug discovery, owing to the significant costs associated with novel candidate identification and other research and development activities 8.

Sulfur is a key component in several vitamin cofactors, sugars and nucleic acids, and plays an important role in regulating translation via the sulfuration of transfer RNA.