2. Academic Validation
  3. Discovery of a Highly Potent, Selective and Efficacious USP7 Degrader for the Treatment of Acute Lymphoblastic Leukemia

Discovery of a Highly Potent, Selective and Efficacious USP7 Degrader for the Treatment of Acute Lymphoblastic Leukemia

  • J Med Chem. 2024 Jul 19. doi: 10.1021/acs.jmedchem.4c01134.
Miaomiao Xu 1 2,  Jingfeng Fu 1 2,  Yuan Pei 1,  Mengna Li 3,  Weijuan Kan 1,  Ruyu Yan 4 2,  Chaoyue Xia 1 2,  Jingkun Ma 1 2 5,  Peipei Wang 3,  Yan Zhang 1 2,  Yue Gao 3,  Yaxi Yang 1 6 4 2,  Yubo Zhou 1 2 5 3,  Jia Li 1 6 4 2 5 3 7,  Bing Zhou 1 6 4 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 5 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Tsuihang New District, Zhongshan, Guangdong 528400, China.
  • 6 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
  • 7 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 39028938 DOI: 10.1021/acs.jmedchem.4c01134
Abstract

USP7 is an attractive therapeutic target for cancers, especially for acute lymphoblastic leukemia (ALL) with wild-type p53. Herein, we report the discovery of XM-U-14 as a highly potent, selective and efficacious USP7 proteolysis-targeting chimera degrader. XM-U-14 achieves DC50 values of 0.74 nM and Dmax of 93% in inducing USP7 degradation in RS4;11 cell lines, and also significantly inhibits ALL cell growth. XM-U-14 even at 5 mg/kg dosed daily effectively inhibits RS4;11 tumor growth with 64.7% tumor regressions and causes no signs of toxicity in mice. XM-U-14 is a promising USP7 Degrader for further optimization for ALL treatment.

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