Session Speaker

Leads and Target Validation for the Prevention and Treatment of Vascular Calcification
Jose Luis Millan
USA

Calcification of the medial layer of arteries is a common and severe condition in patients with chronic kidney disease (CKD), diabetes, obesity and aging that correlates with cardiovascular events and death. Vascular calcification is normally inhibited by extracellular pyrophosphate (PPi) produced by vascular smooth muscle. The key regulator of extracellular PPi is the ectoenzyme tissue-nonspecific alkaline phosphatase, (TNAP), that hydrolyzes PPi thus destroying its ability to suppress calcification. We have shown that TNAP is pathophysiologically upregulated at sites of medial calcification in uremic rat aortas and mouse models of idiopathic infantile arterial calcification, suggesting the putative pathophysiological mechanism that links PPi deficiency to medial calcification in patients with CKD. Using the high throughput screening capabilities of the Conrad Prebys Center for Chemical Genomics at the Burnham Institute for Medical Research we have identified potent inhibitors of TNAP that prevent calcification of aortas in culture. Our current efforts are aimed at validating TNAP as a therapeutic target and improving, via Medicinal Chemistry and structure-activity-relationship studies, the bioavailability and pharmacokinetic properties of novel TNAP inhibitors to enable in vivo testing of the effectiveness of this mechanism-based therapeutic strategy in mouse and rat models of medial calcification.