ST101 Induces a Novel 17kDa APP Cleavage That Precludes Aβ Generation In Vivo

Objective: Inhibiting A beta generation is a prime therapeutic goal for preventing or treating Alzheimer disease. Here we sought to identify any disease-modifying properties of an azaindolizinone derivative, spiro[imidazo[1,2-a]pyridine-3,2-idan]-2(3H)-one (ST101 or ZSET1446). Methods: The effects of ST101 were studied in 3xTg-AD mice and young cynomolgus monkeys using a combination of biochemical and histological analyses. Results: Here we describe that ST101 induces cleavage of APP protein at a novel site, generating a 17kDa C-terminal fragment. This 17kDa APP cleavage product does not appear to be a substrate for either alpha- or beta-secretase, and thus bypasses generation of A beta. ST101 is orally active, efficacious at low doses, improves memory function, and robustly reduces brain A beta in transgenic mice and nonhuman primates. Interpretation: Using rodent and nonhuman primate models, we show that ST101 represents a novel class of small molecules that reduce central nervous system levels of A beta by inducing an alternate pathway of APP cleavage. ANN NEUROL 2011; 69: 831-844