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

Mitachi, Katsuhiko and Kansal, Rita G. and Hevener, Kirk E. and Gillman, Cody D. and Hussain, Syed M. and Yun, Hyun Gi and Miranda-Carboni, Gustavo A. and Glazer, Evan S. and Clemons, William M., Jr. and Kurosu, Michio (2020) DPAGT1 Inhibitors of Capuramycin Analogues and Their Antimigratory Activities of Solid Tumors. Journal of Medicinal Chemistry, 63 (19). pp. 10855-10878. ISSN 0022-2623. PMCID PMC7554145. https://resolver.caltech.edu/CaltechAUTHORS:20200910-143725131

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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).


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acs.jmedchem.0c00545DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554145PubMed CentralArticle
ORCID:
AuthorORCID
Mitachi, Katsuhiko0000-0002-6897-8959
Kansal, Rita G.0000-0001-7232-1602
Hevener, Kirk E.0000-0002-5584-3625
Gillman, Cody D.0000-0002-3548-9200
Hussain, Syed M.0000-0001-8401-3244
Yun, Hyun Gi0000-0002-3508-5791
Miranda-Carboni, Gustavo A.0000-0003-1313-9207
Glazer, Evan S.0000-0002-5796-0542
Clemons, William M., Jr.0000-0002-0021-889X
Kurosu, Michio0000-0003-0092-0619
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.
Funders:
Funding AgencyGrant Number
NIHGM114611
University of TennesseeR079700292
Subject Keywords:Capuramycin analogues, DPAGT1 inhibitor, Antimigratory activity, Snail zinc-finger transcription factors, E-Cadherin, Synergistic effect, Computational chemistry
Issue or Number:19
PubMed Central ID:PMC7554145
Record Number:CaltechAUTHORS:20200910-143725131
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200910-143725131
Official Citation:DPAGT1 Inhibitors of Capuramycin Analogues and Their Antimigratory Activities of Solid Tumors. Katsuhiko Mitachi, Rita G. Kansal, Kirk E. Hevener, Cody D. Gillman, Syed M. Hussain, Hyun Gi Yun, Gustavo A. Miranda-Carboni, Evan S. Glazer, William M. Clemons, and Michio Kurosu. Journal of Medicinal Chemistry 2020 63 (19), 10855-10878; DOI: 10.1021/acs.jmedchem.0c00545
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105314
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Sep 2020 22:11
Last Modified:20 Oct 2020 15:55

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