Development of small‐molecule tau‐SH3 interaction inhibitors that prevent amyloid‐β toxicity

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of dementia and lacks disease‐modifying treatments. Tau‐based therapies are attractive and Tau reduction prevents amyloid‐induced dysfunction in preclinical AD models. Tau reduction also prevents amyloid‐independent dysfunction in diverse disease contexts, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau’s interaction with SH3 domain containing proteins likely underlie mechanisms of amyloid‐induced dysfunction, so we targeted their interaction as a therapeutic strategy.MethodWe previously designed a peptide Tau‐SH3 interaction inhibitor based on the region of Tau that binds FynSH3, and determined that it prevented amyloid‐induced dysfunction in primary neurons. We next completed a high‐throughput screen to identify compounds that inhibit Tau‐Fyn interaction. Here, we studied a top hit from that screen, generated and characterized a series of daughter compounds, and tested whether the compounds prevented amyloid‐induced dysfunction in primary neurons.ResultThe hit compound, SR31627, prevented amyloid‐β toxicity in primary neurons. The medicinal chemistry program resulted in lead compound SR42667, which had five‐fold improved potency and improved drug‐like properties. We found that SR42667 binds Tau, is cell‐permeable, and prevents amyloid‐induced dysfunction.ConclusionWe demonstrate that Tau‐SH3 interactions can be targeted using small molecule inhibitors and that these inhibitors have efficacy for blocking amyloid‐induced dysfunction.