15357163mct200184-sup-239090_2_supp_6396539_qcsyzf.xlsx (1.74 MB)

Supplementary Table S4 from Novel, Selective Inhibitors of USP7 Uncover Multiple Mechanisms of Antitumor Activity In Vitro and In Vivo

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posted on 2023-04-03, 18:03 authored by 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, Paul D. Kassner

Genes whose expression is significantly altered upon USP7 inhibitor treatment of H526 cells.

Funding

USP7 program

History

ARTICLE 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.

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Keywords

Carcinogenesis DNA damage and repair Drug Mechanisms p53 and anticancer drug action Drug Targets Lung Cancer Oncogenes & Tumor Suppressors p53 Small Molecule Agents

Licence

CC BY