2. Academic Validation
  3. Discovery of potent PROTAC degraders of Pin1 for the treatment of acute myeloid leukemia

Discovery of potent PROTAC degraders of Pin1 for the treatment of acute myeloid leukemia

  • Chem Sci. 2024 Feb 28;15(13):5027-5035. doi: 10.1039/d3sc06558h.
Yunkai Shi 1 2,  Minmin Liu 3 4,  Mengna Li 5,  Yiwen Mao 1 2,  Jingkun Ma 3 2 6,  Ruikai Long 1 2,  Miaomiao Xu 3 2,  Yaxi Yang 1 3 2 7,  Wenlong Wang 4,  Yubo Zhou 1 3 2 6 5,  Jia Li 1 3 2 6 7 5,  Bing Zhou 1 3 2 7 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences Hangzhou 310024 China zhoubing2012@hotmail.com.
  • 2 University of Chinese Academy of Sciences 19 Yuquan Road Beijing 100049 China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences 555 Zu Chong Zhi Road Shanghai 201203 China ybzhou@simm.ac.cn jli@simm.ac.cn zhoubing@simm.ac.cn.
  • 4 School of Pharmaceutical Science, Jiangnan University Wuxi 214122 China wenlongwang@jiangnan.edu.cn.
  • 5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine Nanjing 210023 China.
  • 6 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Zhongshan Tsuihang New District Guangdong 528400 China.
  • 7 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery Yantai Shandong 264117 China.
PMID: 38550694 DOI: 10.1039/d3sc06558h
Abstract

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) is overexpressed and/or overactivated in many human cancers and has been shown to play a critical role during oncogenesis. Despite the potential of PIN1 as a drug target, its successful targeting has proved to be challenging. We speculate that only blocking the enzymatic function of PIN1 with inhibitors may not be sufficient to lead to a total loss-of-function. Here, we report the discovery of P1D-34, a first-in-class and potent PROTAC degrader of PIN1, which induced PIN1 degradation with a DC50 value of 177 nM and exhibited potent degradation-dependent anti-proliferative activities in a panel of acute myeloid leukemia (AML) cell lines. In contrast, PIN1 Inhibitor Sulfopin did not show activity. More significantly, P1D-34 could sensitize Bcl-2 Inhibitor ABT-199 in Bcl-2 inhibitor-resistant AML cells, highlighting the potential therapeutic value of targeted PIN1 degradation for Bcl-2 inhibitor-resistant AML treatment. Further mechanism study revealed that P1D-34 led to the up-regulation of ROS pathway and down-regulation of UPR pathway to induce cell DNA damage and Apoptosis. Notably, we further demonstrated that treatment with the combination formula of glucose metabolism inhibitor 2-DG and P1D-34 led to a notable synergistic anti-proliferative effect, further expanding its applicability. These data clearly reveal the practicality and importance of PROTAC as a preliminary tool compound suitable for assessment of Pin1-dependent pharmacology and a promising strategy for AML treatment.

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