Sulindac sulfide (cis-Sulindac sulfide) is a non-steroidal anti-inflammatory compound that has a high affinity for COX-1 and acts as an inhibitor in Ras activation of Raf-1. Sulindac sulfide is a non-competitive inhibitor of gamma-secretase with an IC50 value of 20.2 μM. It is an active metabolite of sulinic acid.

γ42-secretase:20.2 μM , γ42-secretase:20.2 μM, COX-1:1.9 µM, COX-2:1.21 µM, Aldose reductase:279 nM

Treatment with 100 μM of Sulindac sulfide (SSide) induces apoptosis leading to significant reduction in Aβ generation and total protein expression. The IC50 for Aβ42 secretion of SSide is 30.6±2.8 μM. SSide inhibits γ42-secretase activity dose-dependently, with an IC50 of 20.2±2.6 μM. Increasing SSide concentration decreases the slope in the rate vs. enzyme concentration plot, indicating SSide is not an irreversible or pseudo-irreversible inhibitor. After pretreatment of the dialyzed solubilized γ-secretase fraction with SSide and subsequent exposure to CHAPSO buffer without SSide, γ-secretase activity almost fully recovers. This strongly suggests that SSide targets the γ-secretase complex as a reversible inhibitor. [1]

Sulindac sulfide also inhibits aldose reductase, blocking NADPH-dependent reduction of glucose to sorbitol, and reducing type 2 diabetic complications.[2]
Sulindac sulfide inhibits colorectal cancer growth both in vitro and in vivo.[5]