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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Novel, Selective Inhibitors of USP7 Uncover Multiple Mechanisms of Antitumor Activity In Vitro and In Vivo

Yamini M. Ohol, Michael T. Sun, Gene Cutler, Paul R. Leger, Dennis X. Hu, Berenger Biannic, Payal Rana, Cynthia Cho, Scott Jacobson, Steve T. Wong, Jerick Sanchez, Niket Shah, Deepa Pookot, Betty Abraham, Kyle Young, Silpa Suthram, Lisa A. Marshall, Delia Bradford, Nathan Kozon, Xinping Han, Akinori Okano, Jack Maung, Christophe Colas, Jacob Schwarz, David Wustrow, Dirk G. Brockstedt and Paul D. Kassner
Yamini M. Ohol
RAPT Therapeutics, Inc., South San Francisco, California.
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  • For correspondence: yohol@rapt.com pkassner@rapt.com
Michael T. Sun
RAPT Therapeutics, Inc., South San Francisco, California.
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Gene Cutler
RAPT Therapeutics, Inc., South San Francisco, California.
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Paul R. Leger
RAPT Therapeutics, Inc., South San Francisco, California.
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Dennis X. Hu
RAPT Therapeutics, Inc., South San Francisco, California.
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Berenger Biannic
RAPT Therapeutics, Inc., South San Francisco, California.
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Payal Rana
RAPT Therapeutics, Inc., South San Francisco, California.
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Cynthia Cho
RAPT Therapeutics, Inc., South San Francisco, California.
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Scott Jacobson
RAPT Therapeutics, Inc., South San Francisco, California.
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Steve T. Wong
RAPT Therapeutics, Inc., South San Francisco, California.
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Jerick Sanchez
RAPT Therapeutics, Inc., South San Francisco, California.
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Niket Shah
RAPT Therapeutics, Inc., South San Francisco, California.
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Deepa Pookot
RAPT Therapeutics, Inc., South San Francisco, California.
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Betty Abraham
RAPT Therapeutics, Inc., South San Francisco, California.
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Kyle Young
RAPT Therapeutics, Inc., South San Francisco, California.
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Silpa Suthram
RAPT Therapeutics, Inc., South San Francisco, California.
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Lisa A. Marshall
RAPT Therapeutics, Inc., South San Francisco, California.
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Delia Bradford
RAPT Therapeutics, Inc., South San Francisco, California.
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Nathan Kozon
RAPT Therapeutics, Inc., South San Francisco, California.
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Xinping Han
RAPT Therapeutics, Inc., South San Francisco, California.
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Akinori Okano
RAPT Therapeutics, Inc., South San Francisco, California.
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Jack Maung
RAPT Therapeutics, Inc., South San Francisco, California.
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Christophe Colas
RAPT Therapeutics, Inc., South San Francisco, California.
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Jacob Schwarz
RAPT Therapeutics, Inc., South San Francisco, California.
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David Wustrow
RAPT Therapeutics, Inc., South San Francisco, California.
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Dirk G. Brockstedt
RAPT Therapeutics, Inc., South San Francisco, California.
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Paul D. Kassner
RAPT Therapeutics, Inc., South San Francisco, California.
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  • For correspondence: yohol@rapt.com pkassner@rapt.com
DOI: 10.1158/1535-7163.MCT-20-0184 Published October 2020
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Abstract

The deubiquitinase USP7 regulates the levels of multiple proteins with roles in cancer progression and immune response. Thus, USP7 inhibition may decrease oncogene function, increase tumor suppressor function, and sensitize tumors to DNA-damaging agents. We have discovered a novel chemical series that potently and selectively inhibits USP7 in biochemical and cellular assays. Our inhibitors reduce the viability of multiple TP53 wild-type cell lines, including several hematologic cancer and MYCN-amplified neuroblastoma cell lines, as well as a subset of TP53-mutant cell lines in vitro. Our work suggests that USP7 inhibitors upregulate transcription of genes normally silenced by the epigenetic repressor complex, polycomb repressive complex 2 (PRC2), and potentiate the activity of PIM and PI3K inhibitors as well as DNA-damaging agents. Furthermore, oral administration of USP7 inhibitors inhibits MM.1S (multiple myeloma; TP53 wild type) and H526 (small cell lung cancer; TP53 mutant) tumor growth in vivo. Our work confirms that USP7 is a promising, pharmacologically tractable target for the treatment of cancer.

This article is featured in Highlights of This Issue, p. 1957

Footnotes

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

  • Mol Cancer Ther 2020;19:1970–80

  • Received March 12, 2020.
  • Revision received June 18, 2020.
  • Accepted July 30, 2020.
  • Published first August 11, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (10)
October 2020
Volume 19, Issue 10
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Novel, Selective Inhibitors of USP7 Uncover Multiple Mechanisms of Antitumor Activity In Vitro and In Vivo
Yamini M. Ohol, Michael T. Sun, Gene Cutler, Paul R. Leger, Dennis X. Hu, Berenger Biannic, Payal Rana, Cynthia Cho, Scott Jacobson, Steve T. Wong, Jerick Sanchez, Niket Shah, Deepa Pookot, Betty Abraham, Kyle Young, Silpa Suthram, Lisa A. Marshall, Delia Bradford, Nathan Kozon, Xinping Han, Akinori Okano, Jack Maung, Christophe Colas, Jacob Schwarz, David Wustrow, Dirk G. Brockstedt and Paul D. Kassner
Mol Cancer Ther October 1 2020 (19) (10) 1970-1980; DOI: 10.1158/1535-7163.MCT-20-0184

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Novel, Selective Inhibitors of USP7 Uncover Multiple Mechanisms of Antitumor Activity In Vitro and In Vivo
Yamini M. Ohol, Michael T. Sun, Gene Cutler, Paul R. Leger, Dennis X. Hu, Berenger Biannic, Payal Rana, Cynthia Cho, Scott Jacobson, Steve T. Wong, Jerick Sanchez, Niket Shah, Deepa Pookot, Betty Abraham, Kyle Young, Silpa Suthram, Lisa A. Marshall, Delia Bradford, Nathan Kozon, Xinping Han, Akinori Okano, Jack Maung, Christophe Colas, Jacob Schwarz, David Wustrow, Dirk G. Brockstedt and Paul D. Kassner
Mol Cancer Ther October 1 2020 (19) (10) 1970-1980; DOI: 10.1158/1535-7163.MCT-20-0184
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