Ubiquitin-specific protease 7 inhibitors reveal a differentiated mechanism of p53-driven anti-cancer activity

Alan S. Futran; Tao Lu; Katherine Amberg-Johnson; Jiayi Xu; Xiaoxiao Yang; Saidi He; Sarah Boyce; Jeffrey A. Bell; Robert Pelletier; Takao Suzuki; Xianhai Huang; Heng Qian; Liping Fang; Li Xing; Zhaowu Xu; Stephen E. Kurtz; Jeffrey W. Tyner; Wayne Tang; Tao Guo; Karen Akinsanya; David Madge; Kristian K. Jensen

doi:10.1016/j.isci.2024.109693

Ubiquitin-specific protease 7 inhibitors reveal a differentiated mechanism of p53-driven anti-cancer activity

Alan S. Futran, Tao Lu, Katherine Amberg-Johnson, Jiayi Xu, Xiaoxiao Yang, Saidi He, Sarah Boyce, Jeffrey A. Bell, Robert Pelletier, Takao Suzuki, Xianhai Huang, Heng Qian, Liping Fang, Li Xing, Zhaowu Xu, Stephen E. Kurtz, Jeffrey W. Tyner, Wayne Tang, Tao Guo, Karen AkinsanyaDavid Madge, Kristian K. Jensen

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Abstract

The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303. FX1-5303 was used as a chemical probe to study the USP7-mediated regulation of p53 signaling in cells. It demonstrates mechanistic differences compared to MDM2 antagonists, a related class of anti-tumor agents that act along the same pathway. FX1-5303 synergizes with the clinically approved BCL2 inhibitor venetoclax in acute myeloid leukemia (AML) cell lines and ex vivo patient samples and leads to strong tumor growth inhibition in in vivo mouse xenograft models of multiple myeloma and AML. This work introduces new USP7 inhibitors, differentiates their mechanism of action from MDM2 inhibition, and identifies specific opportunities for their use in the treatment of AML.

Original language	English (US)
Article number	109693
Journal	iScience
Volume	27
Issue number	5
DOIs	https://doi.org/10.1016/j.isci.2024.109693
State	Published - May 17 2024

Keywords

Biochemistry
Cancer
Cell biology

ASJC Scopus subject areas

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Futran, A. S., Lu, T., Amberg-Johnson, K., Xu, J., Yang, X., He, S., Boyce, S., Bell, J. A., Pelletier, R., Suzuki, T., Huang, X., Qian, H., Fang, L., Xing, L., Xu, Z., Kurtz, S. E., Tyner, J. W., Tang, W., Guo, T., ... Jensen, K. K. (2024). Ubiquitin-specific protease 7 inhibitors reveal a differentiated mechanism of p53-driven anti-cancer activity. iScience, 27(5), Article 109693. https://doi.org/10.1016/j.isci.2024.109693

Futran, AS, Lu, T, Amberg-Johnson, K, Xu, J, Yang, X, He, S, Boyce, S, Bell, JA, Pelletier, R, Suzuki, T, Huang, X, Qian, H, Fang, L, Xing, L, Xu, Z, Kurtz, SE , Tyner, JW, Tang, W, Guo, T, Akinsanya, K, Madge, D & Jensen, KK 2024, 'Ubiquitin-specific protease 7 inhibitors reveal a differentiated mechanism of p53-driven anti-cancer activity', iScience, vol. 27, no. 5, 109693. https://doi.org/10.1016/j.isci.2024.109693

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abstract = "The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303. FX1-5303 was used as a chemical probe to study the USP7-mediated regulation of p53 signaling in cells. It demonstrates mechanistic differences compared to MDM2 antagonists, a related class of anti-tumor agents that act along the same pathway. FX1-5303 synergizes with the clinically approved BCL2 inhibitor venetoclax in acute myeloid leukemia (AML) cell lines and ex vivo patient samples and leads to strong tumor growth inhibition in in vivo mouse xenograft models of multiple myeloma and AML. This work introduces new USP7 inhibitors, differentiates their mechanism of action from MDM2 inhibition, and identifies specific opportunities for their use in the treatment of AML.",

keywords = "Biochemistry, Cancer, Cell biology",

author = "Futran, {Alan S.} and Tao Lu and Katherine Amberg-Johnson and Jiayi Xu and Xiaoxiao Yang and Saidi He and Sarah Boyce and Bell, {Jeffrey A.} and Robert Pelletier and Takao Suzuki and Xianhai Huang and Heng Qian and Liping Fang and Li Xing and Zhaowu Xu and Kurtz, {Stephen E.} and Tyner, {Jeffrey W.} and Wayne Tang and Tao Guo and Karen Akinsanya and David Madge and Jensen, {Kristian K.}",

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AU - Lu, Tao

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AU - Yang, Xiaoxiao

AU - He, Saidi

AU - Boyce, Sarah

AU - Bell, Jeffrey A.

AU - Pelletier, Robert

AU - Suzuki, Takao

AU - Huang, Xianhai

AU - Qian, Heng

AU - Fang, Liping

AU - Xing, Li

AU - Xu, Zhaowu

AU - Kurtz, Stephen E.

AU - Tyner, Jeffrey W.

AU - Tang, Wayne

AU - Guo, Tao

AU - Akinsanya, Karen

AU - Madge, David

AU - Jensen, Kristian K.

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N2 - The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303. FX1-5303 was used as a chemical probe to study the USP7-mediated regulation of p53 signaling in cells. It demonstrates mechanistic differences compared to MDM2 antagonists, a related class of anti-tumor agents that act along the same pathway. FX1-5303 synergizes with the clinically approved BCL2 inhibitor venetoclax in acute myeloid leukemia (AML) cell lines and ex vivo patient samples and leads to strong tumor growth inhibition in in vivo mouse xenograft models of multiple myeloma and AML. This work introduces new USP7 inhibitors, differentiates their mechanism of action from MDM2 inhibition, and identifies specific opportunities for their use in the treatment of AML.

AB - The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303. FX1-5303 was used as a chemical probe to study the USP7-mediated regulation of p53 signaling in cells. It demonstrates mechanistic differences compared to MDM2 antagonists, a related class of anti-tumor agents that act along the same pathway. FX1-5303 synergizes with the clinically approved BCL2 inhibitor venetoclax in acute myeloid leukemia (AML) cell lines and ex vivo patient samples and leads to strong tumor growth inhibition in in vivo mouse xenograft models of multiple myeloma and AML. This work introduces new USP7 inhibitors, differentiates their mechanism of action from MDM2 inhibition, and identifies specific opportunities for their use in the treatment of AML.

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KW - Cell biology

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Ubiquitin-specific protease 7 inhibitors reveal a differentiated mechanism of p53-driven anti-cancer activity

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