Development of new inhibitors for N-acylethanolamine-hydrolyzing acid amidase as promising tool against bladder cancer.

The endocannabinoid system is a signaling system involved in a wide range of biological effects. Literature strongly suggests the endocannabinoid system role in the pathogenesis of cancer and that its pharmacological activation produces therapeutic benefits. Last research promotes the endocannabinoid system modulation by inhibition of endocannabinoids hydrolytic enzymes instead of direct activation of endocannabinoid receptors to avoid detrimental effects on cognition and motor control. Here we report the identification of N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitors able to reduce cell proliferation and migration and cause cell death on different bladder cancer cell lines. These molecules were designed, synthesized and characterized and active compounds were selected by a fluorescence high-throughput screening method set-up on human recombinant NAAA that also allows to characterize the mechanism of inhibition. Together our results suggest an important role for NAAA in cell migration and in inducing tumor cell death promoting this enzyme as pharmacological target against bladder cancer.