Objective/Rationale:
Our objective is to develop novel drug candidates as therapeutics for Parkinson's disease by selectively targeting and inhibiting the heat shock protein-90 (Hsp90) in the brain. Modulating the activities of Hsp90 alone should produce the benefits that can be derived by targeting two independent proteins, namely, alpha-synuclein and LRRK2, which promote Parkinson's but require Hsp90 for their function. Our approach is pharmacologically important because it will eliminate the need for multiple medications, which often leads to undesired side-effects.
Project Description:
In structure-based drug discovery, three-dimensional images of the drug targets (proteins) bound to potential drug molecules provide vital information to medicinal chemists to design and synthesize compounds rapidly and efficiently. CalAsia Pharmaceuticals and the collaborating institutes will use this approach to understand the interaction of these compounds with Hsp90 and other potential targets. This information will allow the discovery of compounds that will exclusively inhibit the activities of Hsp90 and not any of its close relatives. By doing so, such drug compounds will exhibit significantly reduced side-effects and greater potency.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Currently, the only known drug available for Parkinson’s disease is called levodopa, while other drugs, known as adjuvants, are used to enhance the effects of levodopa without providing any direct clinical benefit. The side-effects and risks of levodopa include indications such as confusion, delusions and hallucinations, as well as involuntary movements called dyskinesia. The selective Hsp90-targeting drugs, which will work through an entirely different mechanism, may overcome these liabilities and promote better therapy.
Anticipated Outcome:
The studies outlined in this project will generate important data on drug compounds to provide a rationale for advancing the concept of selectively modulating Hsp90 for ameliorating the symptoms of PD. If successful, this paradigm may be expanded to the discovery and development of similar drug molecules for treating other diseases such as cancer and infections, where Hsp90 also plays a major role.
Progress Report
The focus of this MJFF funded program is to discover novel brain-permeable Heat Shock Protein 90 inhibitors (Hsp90i), to be developed into a new class of PD therapeutics. Towards achieving the goal of the project, we have identified multiple starting scaffolds that have been evolved into potent low-nanomolar Hsp90is representing a novel chemical class with acceptable CNS ‘drug-like” properties. Currently, a number of seminal experiments are underway that will be critical in achieving the Phase I objectives of this program. Most importantly, pharmacodynamic studies utilizing the tool compound SNX-0723 demonstrated that inhibition of CNS Hsp90 resulted in a robust (~10-fold) induction of CNS Hsp70 expression, thereby establishing proof of principle for our program’s hypothesis and providing a compelling rational to develop Hsp90i to treat PD. Given the favorable biochemical potency and CNS properties of our novel Hsp90i series, we are confident that we will also achieve proof of principle in ongoing pharmacodynamic studies that will position our program for advancement in pre-clinical and developmental studies.
April 2012