by Thomas X. Neenan and Sunghoon Kim
In 2010, the Korean Ministry of Education, Science and Technology (MEST) launched the Global Frontier Project, targeted at solving global challenges in major R&D areas. The Medicinal Bioconvergence Research Center (Biocon) was initiated as one of the three projects with the aim to resolve difficulties during the development of novel drug discovery. Recently celebrating its fifth anniversary, this article briefly describes Biocon’s past, present and future.
The objective of the pharmaceutical industry is to develop and market new drugs, and a useful metric is to correlate the number of new drugs approved to the investment made and to the length of the approval process. In this regard, trends in the industry are not encouraging. While 2014 was a noteworthy year with 41 new drug approvals in the US, the average number of US drug approvals remains steady at approximately 25 new approvals per year. Indeed the FDA’s Center for Drug Evaluation and Research (CDER) reports that the number of new drug applications (NDAs) from sponsors has remained relatively stable over time. The relevant data suggest that the bottleneck to introducing new medical therapies on the shelf is not within the approval agencies, rather the cause lies within the drug development process itself. In this regard, the Pharmaceutical Research and Manufacturers of America (PhRMA) Annual Membership Survey (2014), indicates that the amount of R&D investment by PhRMA Member Companies has doubled from year 2000 to 2014 and a leap from in investment of $26B to $51B while the number of drug approvals in the same period has remained remarkably stable.
A global challenge remains therefore in how to increase the efficacy of the drug discovery process. Biocon began its mission in 2010 with an aim of addressing some of the roadblocks to faster drug discovery. As medicine becomes more personal and stratified, Biocon recognized that the biggest bottleneck in drug discovery is to identify novel therapeutic targets and biomarkers that can accurately address various human diseases. During the first five years, Biocon focused on novel therapeutic target discovery and validation that could be used by industry to develop new therapeutic compounds with a higher probability of success. With the financial support of about 140 million dollars and a projected time-line of 9 years, Biocon has leveraged a unique capability to discover and validate molecular pathways and targets at a level that is possible at few commercial enterprises. In addition, the unique spoke and wheel management structure of Biocon, wherein a central core group of researchers coordinates and directs the activities of a large group of consortium members, allows a rich diversity of talent and expertise to be brought to bear in a focused way (Fig. 1).
While Biocon currently consists of thirty principle investigators in different fields who are affiliated to major domestic universities, institutions and hospitals, it also runs close collaborative work with partners outside of Korea including the US, EU, Japan and China.
Core Science: Research & Development in Biocon
At its R&D core, Biocon focuses on human aminoacyl-tRNA synthetases (ARSs) and their interacting proteins as our primary target space of interest, and explores their potential to address diverse human diseases. These enzymes emerged early in evolution and catalytically link their cognate amino acids to tRNAs for protein synthesis (Fig. 2).
For this reason, ARSs have been traditionally considered as housekeeping proteins solely dedicated to protein synthesis. However, recent new findings from Biocon and other groups world-wide on the novel functions of ARSs are rapidly changing the classical view of these enzymes. Indeed ARSs are emerging as central coordinators linking cell fate determination processes with protein synthesis (Fig. 3).
Aminoacyl-tRNA synthetases initially attracted clinical interest as targets for development of antimicrobial agents. Although these enzymes are well conserved among prokaryotes, significant divergence has occurred between prokaryotic and eukaryotic ARSs, and this difference can be exploited in the discovery of broad-spectrum antibacterial agents. In this regard, an important first example was provided by the antibiotic mupirocin (pseudomonic acid; marketed as Bactroban, GlaxoSmithKline), that selectively inhibits bacterial isoleucyl-tRNA synthetase, but without inhibiting its human homolog (Fig. 4).
In 2014, the US FDA approved a New Drug Application for KERYDIN™, the first oxaborole antifungal from Anacor Pharmaceuticals, for the topical treatment of onychomycosis of the toenails. Onychomycosis is a fungal infection of the nail and nail bed caused by Trichophyton rubrum or Trichophyton mentagrophytes, and it affects approximately 35 million people in the United States.
KERYDINTM, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), inhibits yeast cytoplasmic leucyl-tRNA synthetase. While pathogenic ARSs have been validated as effective targets for anti-infectives, the catalytic inhibition of human ARSs also shows novel therapeutic potential. For instance, halofuginone, a halogenated derivative of the natural product, fabrifuginone, targets the catalytic site of prolyl-tRNA synthetase. This compound shows interesting efficacy in fibrosis, cancer and autoimmune diseases. Additionally, borrelidin, a natural macrolide product, specifically binds to the active site of threonyl-tRNA synthetase. This compound has shown diverse pharmacological activities such as anti-angiogenesis and anti-metastasis.
Finally, recent reports show that the mutations of these enzymes and their interacting factors are associated with human cancers and neurodegenerative diseases. More interestingly, several different human ARSs are secreted as novel cytokines with distinct activities. Atyr Pharmaceuticals (San Diego, USA) who went public in 2015 (NASDAQ: LIFE) have pioneered the discovery and commercialization of specific extracellular signaling regions of ARSs, a class of peptides coined by Atyr Pharmaceuticals as, Physiocrines. ATyr believes that Physiocrines have evolved over time to modulate important cellular pathways by interacting with various types of cells, including immune and stem cells, and that this class of molecules presents a significant therapeutic opportunity in the restoration of affected tissues through natural immuno-modulation.
The number of publications directed towards both basic and translational research, andderived from the catalytic and distinct regulatory activities of ARSs, continues to grow year by year, and spans disease areas as diverse as malaria and Parkinson’s disease. Based on the recent progress on the novel functions and pathologic implications of these ancient enzymes and their associated factors, Biocon considers that this enzyme family has enormous potential and novelty to explore as new drug targets, and for the immediate development of therapeutic entities with distinct applications.
In the period from initiation of the program until the mid-point in 2015, Biocon has rapidly advanced the science in several key areas of ARS technology. A depiction of the key programs is shown below, together with the key high impact paper published for that program (Table 1). In addition, several new targets with different indications are currently under active validation although they are not included in the table.
While a detailed description of all programs is outside the scope of this brief report, certain key achievements can be highlighted:
Glycyl-tRNA synthetase (GRS)
We have demonstrated that secreted human GRS is implicated in immune surveillance against cancer. Specifically, we have shown that GRS is secreted by macrophages and acts against certain tumor types via an interaction with K-cadherin. Injection of purified GRS showed potent anti-tumor activity in vivo. This pathway is likely to have important implications in various cancers, including colon and lung cancer, and suggests GRS and its peptides as a novel resource for cancer immunotherapy.
Lysyl-tRNA synthetase (KRS)
We found that human KRS relocates to the plasma membrane after a laminin signal and enhances the cancer metastatic properties of cancer cells. We have discovered a class of small molecules that specifically binds to a unique cleft of KRS to inhibit its pro-metastatic activity. We believe that this set of observations offers an interesting new pathway to the development of novel drugs against metastasis and some other relevant diseases.
AIMP2 (ARS-interacting multi-functional protein 2) was previously found as an auxiliary factor associated with many different ARSs. We found that AIMP2 can also serve as a potent tumor suppressor with multiple mechanisms, including the activation of p53, a well-studied tumor suppressive protein. While establishing the important role of AIMP2 in tumor suppression over the past decade, we identified AIMP2-DX2, an exon-2 deleted splice variant of AIMP2 that trumps the tumor suppressive nature of AIMP2, and importantly, it is upregulated in specific cancers. Thus, this variant may represent a promising target for many refractory cancers. We have identified potent small molecule candidates that inhibit AIMP2-DX2 with excellent selectivity over the wild type full-length AIMP2.
The core mission of Biocon at the half-way point of our initial funding cycle remains the same, i.e. the discovery and validation of novel therapeutic targets. However, the complexity and diversity of the Biocon programs have led the project to enter a new phase. With a large number of targets identified and, in certain cases, lead programs or directions established, it is clear that several of the programs have progressed to a point where they are ripe for translational evaluation and potential partnering. Additionally, Biocon sees the opportunity through innovative partnering and commercialization strategies to bring the items under development to the clinic.
With excellent research achievements during last five years of Biocon, it is time to put in place a flexible and professional management group that can assess, decide and implement decisions for downstream development that are independent of, but in co-operation with, the underlying scientific mission of Biocon. The action of this group needs to be focused and operated at the standard of global Pharmas since Biocon’s assets in the pipeline are all “first-in-class”. In light of the imperative to move programs from the academic to a translational setting, Biocon has established a TRAnslation and DEvelopment Group (TRADE), comprised of experienced professionals from the global drug development industry. The TRADE group, led by the Biocon’s Chief Business Officer, has a mandate to take Biocon’s inventions and capabilities to global drug development partners. Currently, the TRADE group carries out rigorous assessment of internal Biocon programs with a particular emphasis on matching the target discovery and validation progress of Biocon with unmet market needs or opportunities (Fig. 5).
The TRADE group is unique in having the capability to advance certain projects further downfield than most academic institutions. This capability is again derived from the internal structure of Biocon wherein access can be sought in a collaborative way with research groups specializing in chemistry, pre-clinical development or toxicology. Wherever necessary, Biocon has the financial capability to contract with well-recognized commercial laboratories to confirm data at a level that is appropriate to initiate formal discussion with pharma partners.
The Biocon’s downstream strategy is flexible and pragmatic. We recognize that our academic network is best suited to basic research and to the development of students and future science professionals. However, we constantly seek ways to coordinate our work with the demand and the capabilities of the global pharma industry. We have identified three possible pathways as part of our translational and development strategy:
- Direct partnering of assets to global pharma or biotech partners.
- Spinning off start-up companies that will seek funding for further development.
- Internal development of assets to the IND stage, followed by either of the two pathways above.
In every case, Biocon is driven by the commitment to execute basic science to the highest possible standard. Biocon has constructed integrated teams for full-spectrum target validation, consisting of genomics, proteomics, cellomics, structural biology, bioinformatics, 3D and in vivo disease model and clinical pathology, currently focusing but not restricted to the space of ARSs and the related factors. Our first objective in every project is to map out a new target landscape by adhering to the principle of only publishing complete “discoveries”, with a high impact (Fig. 6).
This strategy is mostly executed by Biocon’s unique “4 +1” team structure (see Fig. 1). Once the landscape has been sufficiently mapped, the TRADE group seeks to identify the effective ways to make them druggable so that we can advance the science in translational directions. This process is executed in a systematic way, namely, by identifying unmet medical needs and also by identifying the best partners or, in certain cases, by carrying the science to the next step(s) so that the value of the target can be readily discerned by prospective partners. In this regard, Biocon is helped in no small part by our distinguished panel of global scientific advisors who have been identified from academia, pharmaceutical industry and clinical practice.
The early years of the Biocon program was devoted to the development of the basic understanding of prospective clinical targets that can be developed from the rich and diverse biology of ARS network. Building a comprehensive network and utilizing the collaborative opportunities that result from our unique management structure has allowed the basic understanding of ARS biology and medicine to progress rapidly over the past five years. While continuing our mission to practice science at the cutting edge, we have increasingly turned our attention to innovative development pathways that can fulfill two key goals: to move our science from the laboratory to the clinic, and to develop pathways and strategies to make our research platform sustainable and expandable as we look to the future. With this vision, Biocon claims to be the world’s first and best target factory.
About the Authors
Thomas X Neenan, Ph.D.
He received his B. Sc (Hons) from the National University of Ireland, his Ph.D. in chemistry from Pennsylvania State University, and was a Fellow at Harvard University. He has 20 years of drug discovery, development, and business experience. Prior to his work with Biocon, he served as the Founder and CTO of Sideris Pharmaceuticals, a clinical stage developer of small molecules for the treatment of diseases of iron overload. Prior to Sideris, he founded and served CEO of Viscus Biologics, Cleveland Ohio, USA. Prior to Viscus, he worked as senior manager at Proxy Biomedical (Galway, Ireland), Warwick Effect Polymers (Coventry, UK) and Trine Pharmaceuticals. He also served as Vice-President, Business Operations for Genzyme Drug Discovery and Development (USA). Currently, he is a board member of Sun BioPharma Inc. USA a pancreatic oncology company
Sunghoon Kim, Ph.D.
Professor of Seoul National University College of Pharmacy and Graduate School of Convergence Technology
Kim received his Bachelor’s degree at Seoul National University College of Pharmacy, Master’s degree at Korea Advanced Institute of Science and Technology (KAIST), Department of Biological Sciences in Korea and PhD degree at Division of Biology and Medicine, Brown University, USA. He then worked as postdoctoral fellow at MIT. Before leading Biocon, he served as a director for “Center for ARS Network” under National Creative Research Initiative of Korea as a Director that formed a ground-breaking work for the core subject of Biocon. He is well-recognized as one of the pioneer in the field of ‘new biology and translational research of human aminoacyl-tRNA synthetases’. He is a recipient of many awards such as Hoam Prize in Medicine by Samsung (2015), the scientist of the year awarded by Korean government (2006). The best scientist award from the National Academy of Science, Korea (2012) and the Korea’s best scientist award from Korean government (2006).