Katsuhiko Mitachi1, Rita G Kansal2, Kirk E Hevener1, Cody D Gillman3, Syed M Hussain2, Hyun Gi Yun3, Gustavo A Miranda-Carboni4, Evan S Glazer2, William M Clemons3, Michio Kurosu1. 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, Tennessee 38163, United States. 2. Department of Surgery and Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, 910 Madison St., Suite 300, Memphis, Tennessee 38163, United States. 3. Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd., Pasadena, California 91125, United States. 4. Department of Medicine, Division of Hematology-Oncology, University of Tennessee Health Science Center, 19 S. Manassas Avenue, Memphis, Tennessee 38163, United States.
Abstract
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).
class="Chemical">Capuramycin displays a class="Chemical">narrow spectrum of antibactn class="Gene">erial 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).
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