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Drug Discovery at MUSC, Part I

Identifying Promising Targets and Compounds

Successfully navigating today’s drug discovery and development process is nothing short of an epic achievement. For every 10,000 to 15,000 compounds that enter the drug discovery pipeline, only one makes it successfully to market.1 Only 3 of 10 drugs that make it to market recoup research and development costs. The average time to market for a new drug is 8 to 12 years, leaving only 8 to 12 years on the typical 20-year patent to commercialize the drug once it has received all regulatory approvals. The cost of shepherding the drug though the pipeline increased from $802 million in 2001 to $1.3 billion in 2005.

In short, the drug discovery process is an extremely high-stakes, high-risk venture that requires long-term research on new compounds, many of which will prove to be dead ends. For researchers, who must surmount all of the hurdles and survive all of the pitfalls along the sometimes tortuous drug development pathway, the challenge can seem daunting  indeed.

Such modern mazes do not yield themselves easily—these are not the days when Greek hero Theseus could defeat the monstrous Minotaur and find his way back out of the maze by simply unraveling a spool of thread. Instead of a spool of thread, highly advanced technology guides the path of modern researchers, helping ensure that they do not start down costly and time-consuming false paths.

Only those well-equipped for this challenge and with an unwavering commitment to see the process through stand a chance of success.

As the only National Cancer Institute (NCI)–designated cancer center in South Carolina and one of fewer than 70 in the nation, MUSC’s  Holling s Cancer Center is taking on the challenge. In the opinion of  Charles D. Smith, PhD, Professor of Pharmaceutical and Biomedical Sciences and Director of the Drug Discover y Shared Resource at MUSC’s Hollings Cancer Center, “the goal of the drug discovery process here is not just to talk about the possibility of developing new drug therapies in grant proposals but to actually take the steps to do it.” Indeed, according to the NCI, its designated centers are “characterized  by scientific excellence and the capability to integrate a diversity of research approaches to focus on the problem of cancer.“2 In its attempts to develop anticancer drugs from bench to bedside, Hollings Cancer Center has definitely demonstrated its commitment to that mission. In addition to the identification and validation of targets performed at many academic medical centers, MUSC and Hollings have instituted high-throughput screening against libraries of chemical compounds; have developed a capacity for lead optimization, long the purview of the pharmaceutical industry; and have even conducted first-in-man clinical trials (for more information on clinical trials of pharmaceutical agents at MUSC, see Part II of this article, to be published in the June/ July issue of Progressnotes).

New Partnerships Between Academia and Industry

Regardless of the depth of available resources, no one successfully navigates the drug discovery process alone. Multidisciplinary collaboration and increasingly cooperation among the pharmaceutical industry, academia and the government provide the optimal opportunity for success.

The Case for Collaboration

With many of its blockbuster patents expiring or soon to expire and its shareholders feeling the pinch, the pharmaceutical industry has loosened its once firm grip on drug discovery, preferring to concentrate its resources on commercializing drugs with some supporting efficacy and safety data, minimizing the risk to their investment. Academic medical institutions, faced with tighter funding from the National Institutes of Health (NIH), have seized the opportunity to play a larger role in the earlier stages of the drug discovery process, especially in the identification and validation of druggable biological targets, before handing a technology off to industry.

Overcoming Barriers to Collaboration

The main barriers to close collaboration between academia and industry in the past have been, from industry’s perspective, less than ironclad patents on intellectual property, and, from the academic institution’s standpoint, conflicts of interest stemming from possible commercial bias. According to Kathleen T. Brady, M.D., PhD, Director of the South Carolina Clinical and Translation Research Institute and Associate Dean for Clinical Research in MUSC’s College of Medicine, the clinical rewards for overcoming these obstacles are significant: “We need to be working with people in industry to speed discovery and speed the pace at which new drugs get into the clinic. It is going to take careful concentration—we can’t let conflict of interest and intellectual property issues make it impossible.”

There would be little point in expending the tremendous time and energy necessary to develop a new drug only to find out that one’s claim on the compound was tenuous. Certainly, no pharmaceutical company will be interested in licensing intellectual property if the patent is not airtight. Just as disastrous would be having the credibility of one’s findings undermined by the perception of a pecuniary interest. Two offices have been expanded recently to help MUSC investigators clear these hurdles to successful collaboration with industry: the Foundation for Research Development and the Conflict of Interest office (for more detail, see inset boxes, “Navigating Intellectual Property Issues” and “Navigating Ethical Issues”).

One way in which researchers manage conflict of interest is by establishing a startup company, which licenses intellectual property from the university. Startup companies accomplish two main goals for investigators. First, they provide separation between their commercial and academic pursuits, thus managing conflict of interest. Second, they allow investigators to pursue special government funding for small businesses (SBIR [small business innovation research] grants) as well as private funding from venture capitalists and angel investors during critical windows of the drug development process when NIH funding is no longer available. Such funding allows researchers to further develop their potential drug compound, making it more attractive to a pharmaceutical company, which would in-license the technology from the startup and pay royalties to the university. The typical handoff to industry occurs after initial efficacy and safety data are available from phase 1 and/or 2 trials.

Benefits of Collaboration

Once barriers regarding intellectual property and conflict of interest have been cleared, the collaboration between industry and academia can be fruitful for both parties. The pharmaceutical company is able to license a promising product already well along the drug development pipeline, reducing the risk associated with the investment needed to take the drug through phase 3 trials and to commercialize it. It can also choose those products best aligned with its markets instead of investing in basic science research that might or might not lead to suitable products. Once some of the risk has been removed from the equation, it may even be willing to invest in orphan diseases, defined as diseases that have not typically attracted pharmaceutical interest because they affect too few people (<200,000 in the United States) or do not garner sufficient profit to justify the outlay of cash needed to see a potential drug from basic research through clinical trial. The primary benefits to the academic medical institution are fulfillment of their mandate to translate basic discoveries into new medical products and the recouping of research dollars that can then be reinvested in other investigative enterprises.

Key Stages in the Drug Discovery Process

Target Identification and Validation

The target for a new drug is typically selected based on extensive basic research on disease pathology, for example comparing a cancerous and a healthy cell and noticing the differences. Ideally, disease-specific structures and functions can then be targeted in the hopes of slowing or preventing disease while leaving healthy cells largely alone. A target can be a gene, receptor, enzyme or any other biological entity that can be demonstrated to influence the course of the disease.

One key advance toward the identification of promising targets has in a way also served as an obstacle. The mapping of the human genome could revolutionize health care and promote personalized medicine, when patients with certain genetic mutations or profiles are given medications specifically designed to be effective for that mutation. However, it has also led to the discovery of thousands of potential new targets, not all of which can (or should) be the focus of drug development. If the promise of personalized medicine is to be realized, the challenge is to choose those targets with most promise so that precious time and money are not wasted on what turns out to be a dead end.

Target assessment is best based on the therapeutic index, according to Stephen P. Ethier, PhD, who co-leads the Hollings Cancer Center’s Cancer Genetics and Molecular Regulation Program and holds the Spaulding-Paolozzi Chair in Breast Cancer Diagnosis, Treatment and Research. The therapeutic index is the ratio of the effect of inactivation of a target on cancer cells vs healthy cells. Most cancer drugs have a therapeutic index of 2:1 or 3:1, meaning that damage to healthy cells will cause treatment to be stopped before all cancer cells have been killed, paving the way for recurrence. According to Dr. Ethier, “with current therapies, we can kill a million or ten million cancer cells, but that still leaves a hundred million behind, which means recurrence is likely.” To be worth the time and investment of bringing a drug to market, the drug should ideally have, according to Dr. Ethier, a therapeutic index of 10:1 or so if it is to have the hope of killing enough cancer cells to prevent recurrence.

To achieve that kind of therapeutic index, Dr. Ethier thinks the best targets are oncogenes, defined as genes that are disrupted at the genomic level, whether through translocation, rearrangement, point mutation or copy number increase. Such oncogenes serve as the drivers of the cascade of effects that lead to cancer. They are, according to Dr. Ethier, “the first domino to fall.” If a drug can be developed to counteract that driver mutation, stopping the problem as it were at its source, it would have far more therapeutic potential than a drug that only intervened much further downstream of that gene, after much damage has already been done.

Once a target has been chosen, it must be validated. Careful validation at this point can save years of wasted time developing a drug that proves to be unsatisfactory because the target is not really causative of the disease. First, the target must be shown to be druggable. If the target is a protein, small-interfering RNA (siRNA) can be used to knock down the expression of that protein and determine the effect of that knockdown on the disease. If the siRNA successfully suppresses the target’s effects, then a drug that would do the same can be predicted to work as well and the target can be assumed to be druggable. Proteomics, or the large-scale study of the structure and function of proteins, can also be used to validate a target. Changes in the expression level of proteins that correlate with disease stage can help determine whether a given target is useful for a specific disease.

High-Throughput Screening

Once a target has been identified and validated, the next step is to find a compound with efficacy against it.

Traditionally, a number of compounds were chosen for testing on the basis of a hypothesis about how the target functioned in the initiation or progression of the disease. Assays were developed and run to determine whether the compound had the expected effect. Because these assays were done by hand, their number was limited by time and laboratory personnel.

With the advent of high-throughput screening, the modern approach is not always driven by a hypothesis. Instead, at MUSC’s Drug Discovery Shared Resource, every member of a 50,000 chemical compound library can be  tested against the target. Investigators work with Drug Discovery staff to develop assays of the target’s activity so that the effect of the various compounds can be assessed. Many investigators have already developed an assay but need help redesigning it for the rapid and reproducible processing needed for high-throughput screening.

In  essence,  high-throughput  screening  uses  automation,  liquid- handling devices and sensitive detectors to perform many assays simultaneously, with the result that 50,000 compounds can be screened in as little as a month (for a simple assay of a pure protein). To further save time, compounds can be mixed before being placed in a well of a 96- to 384-well plate, so that only those providing “hits”are reanalyzed. If a number of hits have a similar chemical structure, then a basic chemotype, or core scaffold, can be deduced for a drug that will appropriately affect the target. This is the lead compound that will be optimized in the next step of the drug discovery process.

Lead Optimization

Many research institutions stop at this point in the drug discovery process, preferring to leave technologically intensive lead optimization to pharmaceutical companies. With the recruitment of Patrick Woster,  PhD, a medicinal chemist who specializes in lead optimization, as Professor of Pharmaceutical & Biomedical Sciences and SmartStateTM Endowed Chair in Drug Discovery, MUSC has entered this competitive arena. Dr. Woster was attracted to MUSC because it had a collaborative environment conducive to entrepreneurialism and “pretty much the entire machinery needed to go through the drug discovery process” aside from lead optimization, for which he provided the “missing link.”

Lead optimization, the process of systematically improving the potency of a lead compound by synthesis and biological evaluation of many related analogues, is important for two main reasons. First, the potency and specificity of the compound can be increased by ensuring that it binds tightly to its target and so has fewer unintended adverse effects and that it possesses appropriate drug-like properties (eg, good absorption, ability to cross biological barriers). Second, by chemically modifying the lead compound structure to improve efficacy and safety, optimization often creates new intellectual property that can be patented. According to Dr. Woster, “As we are making analogues, we almost always make compounds that are unique and haven’t been made before.” Dr. Woster’s Drug Design and Synthesis core facility possesses state-of  the-art  equipment  for  chemical  synthesis  and  compound characterization and has the capacity to simulate the binding of a potential drug to its biological target using computer-assisted design.

Preclinical Studies

After target identification and lead optimization, further studies are necessary to demonstrate the compound’s efficacy against the target, its safety and its  pharmacokinetics/pharmacodynamics  (PK/PD) (ie, absorption, distribution, metabolism and excretion) before the researchers can reach their ultimate goal of compiling the investigational new drug application.

The work of Richard Drake, PhD, allows direct localization and imaging for the PK/PD of a compound, including how well it reaches and is taken up by the targeted tissues and the potential for toxic downstream  metabolites.

He uses an emerging technolog y, matrix-assisted laser desorption/ ionization (MALDI) imaging mass spectrometry, for PK/PD analysis on a newly installed instrument at MUSC. Unlike other currently used techniques, MALDI imaging mass spectrometry can distinguish between the parent compound and its metabolites and can track the spatial distribution of both compound and metabolites in tissue.3

This novel technology allows Dr. Drake to tell “where the drug went to and what form the drug is in because the imaging is linked to the histology and pathology of the tissue.” If an optimized lead is meant to target a given tumor but none of the compound is actually reaching the tumor, then evidently more optimization of the compound is necessary.

Efficacy and safety studies in animal models are an essential step in the drug discovery process. However, investigators at MUSC are working to improve the actual relevance of these findings to human application. According to Dr. Ethier, “the results of preclinical testing are often not predictive of what happens in the clinic.” For the sake of speed, always a consideration given the time limits of patent protection, many researchers take the shortcut of using commercially available cells to quickly grow tumor in a mouse model. The problem, in the opinion of Dr. Ethier, is that “a tumor that grows in 3 weeks bears no relation to human cancer that develops over 10 to 30 years.” Instead, Dr. Ethier proposes primary xenograft models, in which human tumor cells are directly grafted into mice, causing them to develop tumors within a few months. These tumors can then be genomically analyzed, providing more genetic information for the development of clinical trials of targeted therapies. Because the cells are clinically sourced and carefully genotyped, they are likely to be more relevant to actual patient care.

A Case Study of the Preclinical Stages of the Drug Discovery and Development Pipeline: Development of PIM3 Inhibitor

Target Identification

PIM3 is a family of protein kinases that was shown to enhance tumor growth via interaction with another cancer-promoting gene (cMYC) in the late 1980s. It has been identified as an anticancer target by many researchers, including Andrew S. Kraft, M.D., Director of MUSC’s Hollings Cancer Center, because it:

  • Enhances tumor initiation
  • Is elevated in a number of tumor types (eg, prostate cancer, lymphomas)
  • Prevents chemotherapy from killing cancer cells

Clinical and Assessment Commercial

No good PIM3 inhibitors are currently on the market, though a number are in development. Competition is stiff in this arena, with GlaxoSmithKline, Novartis, Genentech, and Abbott all developing PIM inhibitors. Because PIM kinases are well distributed around the body and may play a role not only in cancer but also in immunological disease, stem cell maturation and blood vessel growth, they may be useful clinically for the treatment not only of cancer but of many other diseases as well.

High-Throughput Screening

With the assistance of Dr. Charles Smith and the high- throughput screening facilities at MUSC’s Drug Discovery Shared Resource, Dr. Kraft identified lead compounds showing the strongest  activity  against  his  PIM  target  by  screening  a 50,000-compound library.

Lead Optimization

Once lead compounds had been identified, 40 to 50 analogues were synthesized and optimized by Dr. Smith’s group to identify the best candidate for a drug with activity against PIM3.

Patent Filed

With the help of Foundation for Research Development, Drs. Kraft and Smith filed for a patent on the PIM3 inhibitor.

Startup Company Established

Drs. Kraft and Smith licensed the PIM3 inhibitor from MUSC and founded a startup company, Vortex Biotechnology Corporation, so that they could seek private funding to further develop the drug to make it more attractive to industry.

Preclinical Studies

Dr. Kraft is currently working to amass the safety and efficacy data from animal models necessary for an investigational new drug application to the US Food and Drug Administration. Whether or not this PIM3 inhibitor makes it to clinical trial, his research is helping illuminate the underlying biology of this important family of protein kinases.

Crossing the Chasm of Death

Lest one think that the travails of researchers are over after they have cleared these preclinical stages of the drug discovery and development pipeline, one should be reminded that the next step is making the FDA- regulated leap from basic research to clinical studies across what has been not so affectionately dubbed by otherwise stalwart researchers as the chasm of death.

Part II of this article, which will appear in the June/July issue of Progressnotes, will chronicle how  MUSC  researchers  have  crossed this chasm to make novel compounds available to regional patients, including a first-in-man, first-in-class anticancer compound, and describe the clinical trial phase of the drug development pipeline.


1 The Pharmaceutical Research and Manufacturers of America (PhRMA). 2011 Industry profile. Available at    profile_2011_final.pdf. Accessed March 21, 2012.

2  National Cancer Institute: Office of Cancer Centers. Available at Accessed March 21, 2012.   3 Castellino S, Groseclose MR, Wagner D. MALDI imaging mass spectrometry: bridging biology and chemistry in drug development. Bioanalysis. 2011    Nov;3(21):2427-2441.

This article originally appeared in the April/May 2012 issue of Progressnotes.


The Foundation for Research Development at MUSC guides investigators with novel and clinically relevant technologies on how best to develop the potential of and safeguard the rights to their innovation.


  • Logistical help with the patent application process
  • Counsel on the timing of the patent application (applying too early shortens the window of marketability but applying too late could mean being scooped)
  • Advice about how to write as airtight a patent as possible
  • Assessments of the likelihood of regulatory success
  • Assessments of commercial value
  • Guidance on how to establish startup companies
  • Help procuring funding from venture capitalists or angel investors
  • Marketing of available, patent-protected intellectual properties to potential industry collaborators
  • Help defending a patent against challenge


The Conflict of Interest office ensures that research involving  a collaboration between an MUSC investigator and a pharmaceutical company remains free of commercial bias and that market pressure does not unduly influence the course of that research. It also ensures that, if a faculty startup venture initiates a contract with the University for support of further research related to development of the intellectual property, the venture will assume the full cost of research personnel and resources associated with this agreement, including overhead costs.

To guarantee objectivity, and before any clinical trial can be conducted at MUSC, the Conflict of Interest office, together with the Institutional Review Board, looks at who:

  • Designs the research
  • Conducts the study
  • Reports the results


  • Bringing a drug to market costs an average of $1.3 billion and takes 8-12 years
  • Because of these high stakes, pharmaceutical companies have begun to collaborate more with academic researchers and startup companies for basic science research and development instead of relying only on their in-house discovery capabilities, preferring to license a product that already has supporting efficacy and safety data in order to minimize the riskiness of the investment
  • The goal of industry-academia partnerships is to make novel and effective treatments available to patients sooner
  • MUSC’s Hollings Cancer Center, the only National Cancer Institute–designated cancer center in South Carolina nd one of only 66 in the nation, has invested in cutting-edge technology and recruited experts in virtually every stage of the drug discovery process, including target identification, high-throughput screening against chemical libraries, lead optimization and compound characterization, so that researchers with an identified target will take a project further down the drug development pipeline before handing it off to industry
  • Intellectual property issues and conflict of interest have traditionally been the two main barriers to successful collaboration between industry and academia; MUSC has dedicated resources and established offices to help researchers surmount these obstacles