Drug Repurposing: Recent Publications
Kailash provides an invaluable service to researchers focused on drug repurposing. Below are some recent publications highlighting the importance of drug repurposing and the growth of this industry.
Thayer, Ann M. "Drug Repurposing." Chemical & Engineering News, October 1, 2012.
This fall, at least three conferences will bring together researchers to discuss how finding new uses for known drug compounds can be a strategy for both clinical development and business growth. A few years ago, no such conferences existed. The attendee lists show that interest is widespread among large pharmaceutical companies, small biotech firms, government agencies, academic groups, and nonprofit organizations alike. Although the practice is called by many names—repurposing, repositioning, reusing, and rediscovery—the goal is finding ways to deploy approved drugs or abandoned clinical candidates in new disease areas. "Three key drivers make this very attractive," says Richard K. Harrison, scientific director at the business information firm Thomson Reuters. "The cycle times are shorter, the development costs are less, and the success rates are higher."
Hartwell, Kimberly A., Peter G. Miller, Siddhartha Mukherjee, Alissa R. Kahn, and Tood R. Golub. "Niche-based screening identifies small-molecule inhibitors of leukemia stem cells." Nature Chemical Biology 9 (October 27, 2013): 840-48.
Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.
Shaw, A. T. et al. "Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress." Proceedings of the National Academy of Sciences 108.21 (2011): 8773-8778. ©2011 by the National Academy of Sciences.
Activating K-RAS mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream signaling pathways have been shown to be deregulated by oncogenic K-ras. However, to date there are still no effective targeted therapies for this genetically defined subset of patients. Here we report the results of a small molecule, synthetic lethal screen using mouse embryonic fibroblasts derived from a mouse model harboring a conditional oncogenic K-ras G12D allele. Among the >50,000 compounds screened, we identified a class of drugs with selective activity against oncogenic K-ras–expressing cells. The most potent member of this class, lanperisone, acts by inducing nonapoptotic cell death in a cell cycle- and translation-independent manner. The mechanism of cell killing involves the induction of reactive oxygen species that are inefficiently scavenged in K-ras mutant cells, leading to oxidative stress and cell death. In mice, treatment with lanperisone suppresses the growth of K-ras–driven tumors without overt toxicity. Our findings establish the specific antitumor activity of lanperisone and reveal oxidative stress pathways as potential targets in Ras-mediated malignancies.
Keiser, Michael J., Vincent Setola, John J. Irwin, Christian Laggner, and Bryan L. Roth. "Predicting new molecular targets for known drugs." Nature 462 (November 12, 2009): 175-81.
Although drugs are intended to be selective, at least some bind to several physiological targets, explaining side effects and efficacy. Because many drug–target combinations exist, it would be useful to explore possible interactions computationally. Here we compared 3,665 US Food and Drug Administration (FDA)-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the b 1 receptor by the transporter inhibitor Prozac, the inhibition of the 5-hydroxytryptamine (5-HT) transporter by the ion channel drug Vadilex, and antagonism of the histamine H 4 receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug–target associations were confirmed, five of which were potent (100 nM). The physiological relevance of one, the drug N,N-dimethyltryptamine (DMT) on serotonergic receptors, was confirmed in a knockout mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs.
R. Huang, N. Southall, Y. Wang, A. Yasgar, P. Shinn, A. Jadhav, D.-T. Nguyen, C. P. Austin, The NCGC Pharmaceutical Collection: A Comprehensive Resource of Clinically Approved Drugs Enabling Repurposing and Chemical Genomics. Sci. Transl. Med.3, 80ps16 (2011).
Small-molecule compounds approved for use as drugs may be "repurposed" for new indications and studied to determine the mechanisms of their beneficial and adverse effects. A comprehensive collection of all small-molecule drugs approved for human use would be invaluable for systematic repurposing across human diseases, particularly for rare and neglected diseases, for which the cost and time required for development of a new chemical entity are often prohibitive. Previous efforts to build such a comprehensive collection have been limited by the complexities, redundancies, and semantic inconsistencies of drug naming within and among regulatory agencies worldwide; a lack of clear conceptualization of what constitutes a drug; and a lack of access to physical samples. We report here the creation of a definitive, complete, and nonredundant list of all approved molecular entities as a freely available electronic resource and a physical collection of small molecules amenable to high-throughput screening. (Copyright ©2011, American Association for the Advancement of Science)
Muthyala, Ramaiah. "Orphan/rare drug discovery through drug repositioning." Drug Discovery Today 8.3-4 (2011): 71-76. Print.
There are many, often life-threatening, rare/orphan diseases for which there are few or no therapeutic options. They individually affect few people, but collectively impose very high social and economic burdens. New approaches are bringing big pharma resources to solving the problem through drug repositioning of approved drugs. Advances are being spurred by public and private partnerships, government incentives and awareness brought by patient support groups. Scientific discoveries and new technologies are creating many opportunities for drug repositioning.
Smith, Richard B. "Repositioned drugs: integrating intellectual property and regulatory strategies." Drug Discovery Today 8.3-4 (2011): 131-37. Print.
Successful repositioning of a drug product depends on carefully considering and integrating both intellectual property and regulatory exclusivities. Patent strategies directed to protecting new formulations, indications and methods of use, when combined with strategically repositioned products, can provide effective and long lasting product exclusivity even where the underlying API, and the original formulations, indications and methods of use are off-patent.
Witkowski, Timothy X. "Intellectual property and other legal aspects of drug repurposing." Drug Discovery Today 8.3-4 (2011): 139-43. Print.
Although drug repurposing involves many disciplines to address the technical, medical, regulatory and marketing hurdles for development and commercialization, intellectual property (IP) and other legal matters should not be neglected. Strategies that include IP and legal input can transform an apparently nonviable drug repurposing project into a success. Conversely, a drug repurposing strategy that overlooks appropriate IP and legal analysis might miss significant value opportunities or even result in significant legal liability. Accordingly, a proper drug repurposing project should have expert legal counsel to advise on these issues.