DPAGT1 Inhibitors of Capuramycin Analogues and Their Antimigratory Activities of Solid Tumors
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1.
California Institute of Technology
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).
Additional Information
© 2020 American Chemical Society. Received: April 16, 2020; Published: September 4, 2020. Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM114611. M.K. thanks UTRF (University of Tennessee Health Science Center) for generous financial support (Innovation award R079700292). NMR data were obtained on instruments supported by the NIH Shared Instrumentation Grant. M.K. would like to thank Dr. Michael McNeil (Colorado State University) for providing E. coli B21 WecA strain. The authors gratefully acknowledge Miss Shakiba Eslamimehr and Mr. David Mingle for their efforts in culturing several cancer call lines used in this article. The authors declare no competing financial interest. Dedication: This article is dedicated to the memory of Dr. Isao Kitagawa, Professor Emeritus of Pharmaceutical sciences at Osaka University, an inspirational scientist.Attached Files
Accepted Version - nihms-1626489.pdf
Supplemental Material - jm0c00545_si_001.pdf
Supplemental Material - jm0c00545_si_002.csv
Files
Additional details
- PMCID
- PMC7554145
- Eprint ID
- 105314
- DOI
- 10.1021/acs.jmedchem.0c00545
- Resolver ID
- CaltechAUTHORS:20200910-143725131
- GM114611
- NIH
- R079700292
- University of Tennessee
- Created
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2020-09-10Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field