We identified the Myrica cerifera (Southern Bayberry) extract using a systematic screen as a potent reducer of the structural protein tau, which accumulates in a group of diseases called the "tauopathies". The most prevalent tauopathy is Alzheimer's disease, for which there is renewed interest in the identification of tau- based therapeutic approaches to treat this devastating disease;however mutations in the tau gene are the unequivocal cause of some cases of frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Few therapeutic strategies have targeted the tau protein, despite it being seen as the key factor contributing to neuronal loss in these tauopathies. In fact, depleting tau has shown promise in ameliorating the cognitive impairment observed in mouse models in which either wild-type or mutant tau is overexpressed. Organic extraction, bioactivity-driven fractionation and nuclear magnetic resonance spectroscopy identified the cyclic diarylheptanoid myricanol as one of the main active components from Bayberry involved in lowering tau levels. A previously-uncharacterized enantiomer of myricanol [(S)-myricanol] was the predominant species produced in Myrica cerifera, and found to be primarily responsible for the tau lowering activity. (S)-Myricanol has no violations of the Lipinsk guidelines and, as a natural product, may be subject to active transport processes which may be useful for the oral route of administration. (S)-Myricanol represents a tractable drug candidate for both on its own as a potential therapeutic and as a novel scaffold for further structure activity relationship development. Thus, with the need for emergent anti-tau drugs to treat AD and related tauopathies we will: 1) improve the isolation of (+)-S-myricanol from Myrica cerifera, 2) develop a high-yielding and stereoselective route for the production of synthetic (S)-myricanol which will also be amenable to the preparation of novel derivatives based upon guidance from our preliminary SAR development, and 3) determine the efficacy and conduct eADME (early absorption, distribution, metabolism, and excretion) studies on (S)-myricanol and a limited subset of derivatives. The eADME studies will include metabolism in mouse and human liver microsomes, human plasma protein binding, water solubility testing, broad receptor and ion channel profiling including hERG, and initial pharmacokinetic testing in rats. We would seek to direct our program to identify agents that would be suitable for once-daily, oral administration for the treatment of tauopathies, to increase patient compliance and penetration. We will also continue studies to characterize the mechanism of action of (S)-myricanol using a multipronged approach, taking advantage of tool and reagents that we have uniquely prepared to investigate tau biochemistry. Ultimately these studies could provide a novel series of natural-product derived tau-lowering agents as probes for pre-clinical evaluation in animal models characteristic of the tauopathies, and provide in vivo proof of concept validation to serve as a springboard into Phase II of the STTR program for eventual preclinical development and commercialization.
The structural protein tau accumulates in more than 15 neurodegenerative diseases, collectively termed tauopathies, with the most common being Alzheimer's disease. Despite this fact, only one drug currently in clinical trials targets the tau protein specifically. Here, using newly identified chemical tools based our discovery of the unexpected tau lowering properties of the natural product (S)-myricanol we will explore whether the tau protein can be cleared from the brain in vivo and seek to identify drug candidates that are beneficial for the treatment of tauopathies including Alzheimer's disease.
|Martin, Mackenzie D; Baker, Jeremy D; Suntharalingam, Amirthaa et al. (2016) Inhibition of Both Hsp70 Activity and Tau Aggregation in Vitro Best Predicts Tau Lowering Activity of Small Molecules. ACS Chem Biol 11:2041-8|
|Martin, Mackenzie D; Calcul, Laurent; Smith, Courtney et al. (2015) Synthesis, stereochemical analysis, and derivatization of myricanol provide new probes that promote autophagic tau clearance. ACS Chem Biol 10:1099-109|