FK778, A Synthetic Malononitrilamide

ABSTRACT

FK778 is a synthetic malononitrilamide (MNA) that has been demonstrated to have both both immunosuppressive and anti-proliferative activities. The MNAs inhibit both T-cell and B-cell function by blocking de novo pyrimidine synthesis, through blockade of the pivotal mitochondrial enzyme dihyroorotic acid dehydrogenase (DHODH), and the inhibition of tyrosine kinase activity. FK778 has been demonstrated to prevent acute allograft rejection in multiple experimental transplant models in rodents, dogs and primates and to be effective in the rat model of chronic renal allograft rejection. In addition, FK778 has been shown to prevent vascular remodeling after mechanical intimal injury via a mechanism which may be related to tyrosine kinase inhibitory activity in vascular smooth muscle cells. Another intriguing activity of the MNA family is the ability to block replication of members of the Herpes virus family with in vitro evidence that of efficacy against cytomegalovirus (CMV) and polyoma virus, important pathogens in the transplant recipient. FK778 is currently being explored in a number of trials in solid organ transplant recipients.