Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors

Andrea M. Zuhl (), Charles E. Nolan, Michael A. Brodney, Sherry Niessen, Kevin Atchison, Christopher Houle, David A. Karanian, Claude Ambroise, Jeffrey W. Brulet, Elizabeth M. Beck, Shawn D. Doran, Brian T. O’Neill, Christopher W. am Ende, Cheng Chang, Kieran F. Geoghegan, Graham M. West, Joshua C. Judkins, Xinjun Hou, David R. Riddell and Douglas S. Johnson ()
Additional contact information
Andrea M. Zuhl: Pfizer Worldwide Research and Development
Charles E. Nolan: Pfizer Worldwide Research and Development
Michael A. Brodney: Pfizer Worldwide Research and Development
Sherry Niessen: Worldwide Medicinal Chemistry
Kevin Atchison: Pfizer Worldwide Research and Development
Christopher Houle: Pfizer Worldwide Research and Development
David A. Karanian: Pfizer Worldwide Research and Development
Claude Ambroise: Pfizer Worldwide Research and Development
Jeffrey W. Brulet: Pfizer Worldwide Research and Development
Elizabeth M. Beck: Pfizer Worldwide Research and Development
Shawn D. Doran: Pfizer Worldwide Research and Development
Brian T. O’Neill: Worldwide Medicinal Chemistry
Christopher W. am Ende: Worldwide Medicinal Chemistry
Cheng Chang: Pfizer Worldwide Research and Development
Kieran F. Geoghegan: Worldwide Medicinal Chemistry
Graham M. West: Worldwide Medicinal Chemistry
Joshua C. Judkins: Pfizer Worldwide Research and Development
Xinjun Hou: Pfizer Worldwide Research and Development
David R. Riddell: Pfizer Worldwide Research and Development
Douglas S. Johnson: Pfizer Worldwide Research and Development

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer’s disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein. Through a series of exploratory toxicology studies, we show that quantifying CatD target engagement in cells with the probe is predictive of ocular toxicity in vivo. Taken together, our findings designate off-target inhibition of CatD as a principal driver of ocular toxicity for BACE1 inhibitors and more generally underscore the power of chemical proteomics for discerning mechanisms of drug action.

Date: 2016
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DOI: 10.1038/ncomms13042

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