Selective n-glycan biosynthesis inhibitors towards antimetastatic drug discovery - cancer metastasis is responsible for approximately 90% of cancer-related deaths

The National Cancer Institute awarded the University of Tennessee Health Science Center $389,215 on August 25, 2026, under the Cancer Treatment Research program (CFDA 93.395) to develop selective N-glycan biosynthesis inhibitors targeting metastatic triple-negative breast cancer.

The research employs structure-guided medicinal chemistry to optimize DPAGT1 (dolichyl-phosphate N-acetylglucosaminephosphotransferase 1) inhibitors, the first committed enzyme in N-glycan biosynthesis. The project builds on the lead compound APPB, a muraymycin A1 analogue that has demonstrated antitumor and antimetastatic efficacy in MDA-MB-231 xenograft and patient-derived xenograft models. Work includes pharmacological optimization of lead compounds; biochemical, cellular, ex vivo, and in vivo evaluation; therapeutic efficacy assessment in validated mouse models of triple-negative breast cancer; and mechanistic studies examining how selective DPAGT1 inhibition suppresses epithelial-mesenchymal transition and disrupts oncogenic N-glycosylation-dependent signaling. The project runs through July 31, 2031, with performance in Memphis, Tennessee.

This is a Project Grant, a standard NIH R01 award mechanism for investigator-initiated research in cancer treatment modalities.

Triple-negative breast cancer (tnbc), which accounts for 15-20% of breast cancers, is an aggressive subtype characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. As a result, tnbc patients have limited treatment options and remain at high risk for recurrence and metastatic disease, underscoring the need for new targeted therapies. Our laboratory has identified selective inhibitors of dolichyl-phosphate n-acetylglucosaminephosphotransferase 1 (DPAGT1), the first committed enzyme in n-glycan biosynthesis, as a promising therapeutic strategy for solid tumors. We developed appb, a simplified muraymycin A1 analogue incorporating a "water-soluble lipid mimetic", which exhibits potent antiproliferative and antimetastatic activity while sparing normal/healthy cells. Appb has demonstrated significant antitumor efficacy in MDA-MB-231 xenograft and HCI-012 patient-derived xenograft (PDX) models and suppresses metastatic progression in vivo. We hypothesize that pharmacological optimization of selective DPAGT1 inhibitors will produce drug-like candidates with improved potency, pharmacokinetic properties, and therapeutic efficacy. The overall objective of this project is to develop next-generation DPAGT1 inhibitors for the treatment of metastatic tnbc. We will employ structure-guided medicinal chemistry to optimize lead compounds and evaluate their pharmacological properties using established biochemical, cellular, EX vivo, and in vivo models. Therapeutic efficacy will be assessed in validated mouse models of tnbc, with emphasis on inhibition of tumor growth and metastatic dissemination. Mechanistic studies will define how selective DPAGT1 inhibition suppresses epithelial-mesenchymal transition (EMT), disrupts oncogenic n-glycosylation-dependent signaling, induces persistent endoplasmic reticulum stress, and activates apoptosis. These mechanisms are fundamentally distinct from those of the nonspecific cytotoxic natural product tunicamycin, supporting the potential for an improved therapeutic index. Successful completion of this project will establish selective DPAGT1 inhibition as a novel strategy for treating metastatic tnbc, identify preclinical development candidates with favorable pharmacological properties, and provide a strong foundation for the development of safe, targeted anticancer therapies for metastatic breast cancers.