Figure 2. Bridging the gap between academic research and drug discovery
Contact
Dr. Kevin Hodgetts
Director of The Laboratory for Drug Discovery in Neurodegeneration
65 Landsdowne Street
Cambridge, Massachusetts 02139
U.S.A.
Telephone: 617-768-8640
Email: khodgetts@partners.org
Lead optimization is a complex, non-linear process used to refine the chemical structure of a confirmed hit to improve its drug characteristics and selectivity, and its goal is to produce a preclinical drug candidate that can be tested in vivo. Lead optimization employs a combination of empirical, combinatorial, and rational approaches that optimizes leads through a continuous, multi-step process based on knowledge gained at each stage. In this phase, a set of compounds related to the original lead (called analogs) are synthesized and tested to establish structure activity relationships (SAR). Often, due to its inherent complexity, it is lead optimization that represents the bottleneck of a drug discovery program.
The LDDN was established to discover chemical agents from which a new generation of drugs to treat neurodegenerative diseases could be developed. Since then, the LDDN has succeeded in helping to transform discoveries in the basic biology of neurodegeneration into opportunities for drug discovery. Each drug discovery program at the LDDN begins when a principal investigator approaches the LDDN about initiating a collaboration based upon the discoveries in neurodegenerative diseases in his/her laboratory. When such a partnership arises, the LDDN’s contribution is the discovery of molecules that can be used as tools for both basic research and as lead structures in the discovery and development of new therapeutics.
With big pharma’s mass exodus from the early stages of drug discovery, primarily due to its unwillingness to take financial risks early on in the process, it is incumbent upon academia to step in and fill the void left by its absence. Given the slow progress in CNS drug discovery, particularly in neurodegeneration, we must be stalwart in our commitment to our scientific research and continue to move forward with the goal of developing therapeutics for neurological diseases by achieving greater innovation in drug discovery. It is undeniable that the strengths of academia lay in fundamental scientific discovery, while the strengths of industry lay in preclinical development, clinical trials and commercialization. The mission of the LDDN is, therefore, to build a bridge between the basic biology discoveries in academia and the engagement of a pharmaceutical industry partner who has the resources and the know-how required to bring new therapies to wide-spread use.
Basic biology and “hypothesis-driven” science are the essential backbones in the discovery and development of new therapies. However, the primary misconception is that these discoveries and advancements will be translated into therapies in a timely manner. The reality, however, is that this rarely is the case. While, over the last twenty years, there have been multiple high-profile publications offering alternatives to the “amyloid-hypothesis of Alzheimer’s Disease,” and while even headlines in the popular press have announced that a cure for Alzheimer’s Disease is in sight, these optimistic predictions have not yet been brought to fruition, largely because the pharmaceutical industry remains unwilling to take risks on un-validated new targets. Indeed, such reports rarely inspire serious and significant research outside of the originating academic laboratories. As a result, significant time-lags and gaps exist between our understandings of disease, mechanisms, and molecular targets. Add to this the pharmaceutical industry’s assertion that a complete mechanistic understanding is required before entering into discovery research on a “new” target, and it is hardly surprising that little progress has been forthcoming.
Indeed, the amyloid-hypothesis of Alzheimer’s Disease, itself, is an illustrative example (Figure 1). While Alzheimer’s initial discovery of the disorder took place in 1906, it took nearly 80 years before Glenner identified Ab as the primary component of amyloid plaques in AD in 1984. Subsequent discoveries by Dennis Selkoe in 1992 pointed to the APP-to-Ab conversion as a possible therapeutic target and to the potential that simple cell culture systems could be used to screen and identify molecules that blocked the formation of Ab. Despite the compelling evidence surrounding Ab as a viable target for intervention and the availability of a screening system in 1992, serious and significant interest by industry did not begin until after the proteases responsible for Ab generation, b- and g-secretase were discovered in 1999. Compounds from this approach are, only now, being evaluated in early clinical trials. The seven year gap between the generation of cellular models and the entry of pharma into this field is a consequence of the industry’s insistence on requiring extensive mechanistic evidence before even beginning discovery efforts on new approaches. Even if the b- and g-secretase approaches ultimately prove successful in the clinic, it likely will not be until the 2020s that these treatments are available for prescription. As stated above, academia cannot and should not wait on industry to invest in science; it is for academic institutions like the LDDN to continue to explore and advance scientific discoveries, which will, ultimately, be so innovative as to entice industry to partner with the LDDN and invest in further investigation, clinical trials, etc.
Figure 1. Timeline for the discovery of amyloid therapies in Alzheimer’s Disease
The Gap in Drug Discovery
Harvard
Medical School
Brigham and
Women's Hospital
Laboratory for Drug Discovery in Neurodegeneration