Biochemical Mapping of the GSM Binding Site of Novel Pyridazine-Derived Small Molecule Gamma-Secretase Modulators

2019

Alzheimer’s disease is a huge health problem that imposes a severe social and economic burden; in the absence of an effective disease-modifying treatment, it is projected to become a dominant source of health care expenditures over the next several decades. Unfortunately, existing treatments are palliative, providing only temporary symptomatic benefit. Through a number of Cure Alzheimer’s Fund and National Institutes of Health awards, we have discovered and developed a series of highly potent compounds known as gamma secretase modulators. These compounds have been shown to inhibit the formation of amyloid beta 42, the primary component of the amyloid plaques thought to play a major role in the initiation and progression of the disease. Despite the therapeutic promise of this series of GSMs, such as BPN-15606 and UCSD/MGH-776890, little is known about how these compounds work. The research described in this interim report, combined with studies planned for year 2, provides critical insight into the complex mechanisms of how this enzyme produces amyloid beta 42 and how GSMs are able to attenuate the production of this neurotoxic species.

2017

A promising series of pyridazine-derived gamma-secretase modulators (GSMs) have been discovered in our labs at the University of California, San Diego and Massachusetts General Hospital that inhibit the formation of the aggregation-prone amyloid beta 42 peptide in favor of shorter, less pathogenic amyloid beta isoforms. Despite the development of numerous potent GSMs, the molecular target and the mechanism of action of these compounds remain nascent. Previously, we synthesized an active GSM-photoaffinity probe based on our GSM currently undergoing preclinical development to be used in cross-linking studies in order to identify the binding site of these ligands within the gamma-secretase enzyme. Initial studies have demonstrated that our novel GSMs selectively bind to the PS1-NTF domain of the gamma-secretase enzymatic complex. Additional experiments have been planned, with the goal of broadening our understanding of these specific target-ligand interactions by mapping of the bind site of our novel GSMs. The identification of the critical sites of contact will foster an improved understanding of the mechanism by which these therapeutically relevant small molecules affect the production of amyloid beta peptides. Furthermore, these experiments then will permit the use of in silico modeling of the dynamics of enzymatic processing of amyloid precursor protein (APP), as well as other important substrates of gamma-secretase. The successful mapping of the GSM binding site within gamma-secretase in conjunction with the recently attained 3.4 Å resolution cryo-EM structure of gamma-secretase will enable compound docking facilitating rational structural modifications in order to identify more potent, as well as novel, alternative clinical candidates in the event of any untoward safety/toxicological events in the upcoming clinical trials with BPN-15606.