Development of Novel DPAGT1 Inhibitors based on Tunicamycin V and its Homologous Structures

Abstract

The central role of dolichyl-phosphate N-acetylglucosamine-phosphotransferase 1 (DPAGT1) suggests that its inhibition could affect the glycosylation of many essential biological systems. The tunicamycins are the only DPAGT1 inhibitors known and biochemical studies with these DPAGT1 inhibitors are limited by their promiscuous toxicities. The tunicamycins kill a wide range of cancer and healthy cells in a non-selective manner. In sharp contrast, selective DPAGT1 inhibitors identified in our program display strong cytostatic effect against solid cancers which require the overexpression of DPAGT1 in their progression, but do not affect cell viability of healthy cells. The identified DPAGT1 inhibitors possess impressive anti-metastatic ability in various solid cancer cell lines and induce their mitochondrial structural changes. This review summarizes our discovery of novel DPAGT1 inhibitors with drug-like properties and proof-of-pharmaceutical concept studies of a novel DPAGT1 inhibitor in xenograft and orthotopic anticancer mouse models.