DPAGT1 Inhibitors of Capuramycin Analogues and Their Antimigratory Activities of Solid Tumors

Capuramycin displays a narrow spectrum
of antibacterial activity
by targeting bacterial translocase I (MraY). In our program of development
of new N-acetylglucosaminephosphotransferase1 (DPAGT1)
inhibitors, we have identified that a capuramycin phenoxypiperidinylbenzylamide
analogue (CPPB) inhibits DPAGT1 enzyme with an IC50 value
of 200 nM. Despite a strong DPAGT1 inhibitory activity, CPPB does
not show cytotoxicity against normal cells and a series of cancer
cell lines. However, CPPB inhibits migrations of several solid cancers
including pancreatic cancers that require high DPAGT1 expression in
order for tumor progression. DPAGT1 inhibition by CPPB leads to a
reduced expression level of Snail but does not reduce E-cadherin expression
level at the IC50 (DPAGT1) concentration. CPPB displays
a strong synergistic effect with paclitaxel against growth-inhibitory
action of a patient-derived pancreatic adenocarcinoma, PD002: paclitaxel
(IC50: 1.25 μM) inhibits growth of PD002 at 0.0024–0.16
μM in combination with 0.10–2.0 μM CPPB (IC50: 35 μM).