Editor’s note: this is the second in a series of posts highlighting drug screening studies in our Conrad Prebys Center for Chemical Genomics. Read the first post here.
Calcification of the medial layer of arteries is increasingly recognized as an important clinical problem. Medial vascular calcification (MVC) is the major cause of morbidity and mortality in generalized arterial calcification of infancy (GACI), and contributes to cardiovascular deterioration in Kawasaki disease (KD), chronic kidney disease (CKD), as well as in diabetes, obesity, and aging. MVC is thought to result from decreased circulating levels of the mineralization inhibitor, inorganic pyrophosphate (PPi).
Researchers at Sanford-Burnham have revealed that the development of MVC in mouse and rat models is accompanied by up-regulation of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme whose primary function is to hydrolyze PPi, and thus, crucial in determining where mineralization occurs. Preliminary data have proven that upregulation of TNAP is sufficient to cause MVC and Sanford-Burnham scientists have developed potent drug-like inhibitors of TNAP.
Taking advantage of the resources and researchers in Sanford-Burnham’s Conrad Prebys Center for Chemical Genomics, the team optimized the properties of a TNAP inhibitor and more than 294 compounds were synthesized. As a result, they developed several drug-like lead compounds that show greatly optimized pharmacokinetic properties compared to the original parent inhibitor.
Targeting TNAP function appears to be the most promising therapeutic approach for patients suffering from MVC. Currently, doctors mostly treat the symptoms of MVC, but not the underlying pathogenesis. Current data indicate that upregulation of TNAP is the key effector molecule in the pathogenesis of MVC and provides a rational target for treatment. Whether TNAP inhibitors will prove to be more efficacious and safer than current treatments remains to be established.
The study was led by José Luis Millán, Ph.D., professor in the Genetic Disease Program in Sanford-Burnham’s Sanford Children’s Health Research Center.