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Metabolism and Chemical Biology

Bromodomain-Selective BET Inhibitors Are Potent Antitumor Agents against MYC-Driven Pediatric Cancer

P. Jake Slavish, Liying Chi, Mi-Kyung Yun, Lyudmila Tsurkan, Nancy E. Martinez, Barbara Jonchere, Sergio C. Chai, Michele Connelly, M. Brett Waddell, Sourav Das, Geoffrey Neale, Zhenmei Li, William R. Shadrick, Rachelle R. Olsen, Kevin W. Freeman, Jonathan A. Low, Jeanine E. Price, Brandon M. Young, Nagakumar Bharatham, Vincent A. Boyd, Jun Yang, Richard E. Lee, Marie Morfouace, Martine F. Roussel, Taosheng Chen, Daniel Savic, R. Kiplin Guy, Stephen W. White, Anang A. Shelat and Philip M. Potter
P. Jake Slavish
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Liying Chi
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Mi-Kyung Yun
2Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Lyudmila Tsurkan
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Nancy E. Martinez
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Barbara Jonchere
3Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Sergio C. Chai
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Michele Connelly
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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M. Brett Waddell
4Molecular Interaction Analysis Shared Resource, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Sourav Das
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Geoffrey Neale
5Hartwell Center, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Zhenmei Li
2Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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William R. Shadrick
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Rachelle R. Olsen
6Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Kevin W. Freeman
6Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Jonathan A. Low
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Jeanine E. Price
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Brandon M. Young
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Nagakumar Bharatham
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Vincent A. Boyd
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Jun Yang
7Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Richard E. Lee
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Marie Morfouace
3Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Martine F. Roussel
3Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Taosheng Chen
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Daniel Savic
8Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
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R. Kiplin Guy
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Stephen W. White
2Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Anang A. Shelat
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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  • For correspondence: phil.potter@stjude.org anang.shelat@stjude.org
Philip M. Potter
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
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  • For correspondence: phil.potter@stjude.org anang.shelat@stjude.org
DOI: 10.1158/0008-5472.CAN-19-3934 Published September 2020
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Abstract

Inhibition of members of the bromodomain and extraterminal (BET) family of proteins has proven a valid strategy for cancer chemotherapy. All BET identified to date contain two bromodomains (BD; BD1 and BD2) that are necessary for recognition of acetylated lysine residues in the N-terminal regions of histones. Chemical matter that targets BET (BETi) also interact via these domains. Molecular and cellular data indicate that BD1 and BD2 have different biological roles depending upon their cellular context, with BD2 particularly associated with cancer. We have therefore pursued the development of BD2-selective molecules both as chemical probes and as potential leads for drug development. Here we report the structure-based generation of a novel series of tetrahydroquinoline analogs that exhibit >50-fold selectivity for BD2 versus BD1. This selective targeting resulted in engagement with BD-containing proteins in cells, resulting in modulation of MYC proteins and downstream targets. These compounds were potent cytotoxins toward numerous pediatric cancer cell lines and were minimally toxic to nontumorigenic cells. In addition, unlike the pan BETi (+)-JQ1, these BD2-selective inhibitors demonstrated no rebound expression effects. Finally, we report a pharmacokinetic-optimized, metabolically stable derivative that induced growth delay in a neuroblastoma xenograft model with minimal toxicity. We conclude that BD2-selective agents are valid candidates for antitumor drug design for pediatric malignancies driven by the MYC oncogene.

Significance: This study presents bromodomain-selective BET inhibitors that act as antitumor agents and demonstrates that these molecules have in vivo activity towards neuroblastoma, with essentially no toxicity.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Cancer Res 2020;80:3507–18

  • ↵†Deceased.

  • Received December 17, 2019.
  • Revision received April 27, 2020.
  • Accepted June 29, 2020.
  • Published first July 10, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Research: 80 (17)
September 2020
Volume 80, Issue 17
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Bromodomain-Selective BET Inhibitors Are Potent Antitumor Agents against MYC-Driven Pediatric Cancer
P. Jake Slavish, Liying Chi, Mi-Kyung Yun, Lyudmila Tsurkan, Nancy E. Martinez, Barbara Jonchere, Sergio C. Chai, Michele Connelly, M. Brett Waddell, Sourav Das, Geoffrey Neale, Zhenmei Li, William R. Shadrick, Rachelle R. Olsen, Kevin W. Freeman, Jonathan A. Low, Jeanine E. Price, Brandon M. Young, Nagakumar Bharatham, Vincent A. Boyd, Jun Yang, Richard E. Lee, Marie Morfouace, Martine F. Roussel, Taosheng Chen, Daniel Savic, R. Kiplin Guy, Stephen W. White, Anang A. Shelat and Philip M. Potter
Cancer Res September 1 2020 (80) (17) 3507-3518; DOI: 10.1158/0008-5472.CAN-19-3934

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Bromodomain-Selective BET Inhibitors Are Potent Antitumor Agents against MYC-Driven Pediatric Cancer
P. Jake Slavish, Liying Chi, Mi-Kyung Yun, Lyudmila Tsurkan, Nancy E. Martinez, Barbara Jonchere, Sergio C. Chai, Michele Connelly, M. Brett Waddell, Sourav Das, Geoffrey Neale, Zhenmei Li, William R. Shadrick, Rachelle R. Olsen, Kevin W. Freeman, Jonathan A. Low, Jeanine E. Price, Brandon M. Young, Nagakumar Bharatham, Vincent A. Boyd, Jun Yang, Richard E. Lee, Marie Morfouace, Martine F. Roussel, Taosheng Chen, Daniel Savic, R. Kiplin Guy, Stephen W. White, Anang A. Shelat and Philip M. Potter
Cancer Res September 1 2020 (80) (17) 3507-3518; DOI: 10.1158/0008-5472.CAN-19-3934
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