DPAGT1—Perspective as an Anticancer Drug Target

Abstract

Tunicamycins trigger endoplasmic reticulum (ER) stress by inhibiting DPAGT1 (dolichyl-phosphate N-acetylglucosamine-phosphotransferase 1): the rate-limiting enzyme that initiates N-glycan biosynthesis. Aberrant N-glycan branching is a hallmark of many solid tumors, and distinct cancer-associated N-glycan structures have been identified. Evidence shows that tunicamycins suppress key oncogenic processes, including proliferation, apoptosis resistance, metastasis, and angiogenesis. Yet their high systemic toxicity and lack of selectivity have precluded therapeutic application, and the structural complexity of tunicamycins has hindered chemical modification to mitigate these liabilities. No clinically translatable antitumor efficacy has been demonstrated in animal models. This review underscores the emergence of DPAGT1 as a novel and tractable anticancer target, outlining milestones in the discovery of selective inhibitors and their potential to transform cancer therapy. We discuss how advances in DPAGT1 inhibitor design may overcome limitations of tunicamycins and pave the way toward glycosylation-targeted oncology therapeutics.