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

文献类型：期刊论文

作者Shi, Yunkai5,7; Liu, Minmin4,6; Li, Mengna1; Mao, Yiwen5,7; Ma, Jingkun3,5,6; Long, Ruikai5,7; Xu, Miaomiao5,6; Yang, Yaxi2,5,6,7; Wang, Wenlong4; Zhou, Yubo1,3,5,6,7
刊名CHEMICAL SCIENCE
出版日期2024-03-27
卷号15期号:13页码:5027-5035
ISSN号2041-6520
DOI10.1039/d3sc06558h
通讯作者Wang, Wenlong(wenlongwang@jiangnan.edu.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Zhou, Bing(zhoubing2012@hotmail.com)
英文摘要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. The first PROTAC degrader of Pin1 was developed and exhibited potent degradation-dependent anti-proliferative activities in acute myeloid leukemia cells.
WOS关键词STRUCTURE-BASED DESIGN ; PROTEIN-DEGRADATION ; ISOMERASE PIN1 ; CANCER ; PROTEOLYSIS ; BINDING ; TARGET
资助项目Natural Science Foundation of Shanghai Municipality[81973166] ; Natural Science Foundation of Shanghai Municipality[81821005] ; National Natural Science Foundation of China[22XD1424600] ; Science and Technology Commission of Shanghai Municipality[22ZR1474100] ; Natural Science Foundation of Shanghai[SYS202205] ; Taishan Scholar Foundation of Shandong Province, Shandong Laboratory Program[ZR2023JQ028] ; Shandong Provincial Natural Science Foundation[2019B090904008] ; Guangdong High-Level New RD Institute[2021B0909050003] ; Guangdong High-Level Innovative Research Institute
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001180066500001
出版者ROYAL SOC CHEMISTRY
源URL[http://119.78.100.183/handle/2S10ELR8/310175]  
专题新药研究国家重点实验室
通讯作者Wang, Wenlong; Zhou, Yubo; Li, Jia; Zhou, Bing
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
3.Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Chinese Acad Sci, Zhongshan Tsuihang New Di 528400, Guangdong, Peoples R China
4.Jiangnan Univ, Sch Pharmaceut Sci, Wuxi 214122, Peoples R China
5.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
6.Shanghai Inst Mat Med, Chinese Acad Sci, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
7.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Shi, Yunkai,Liu, Minmin,Li, Mengna,et al. Discovery of potent PROTAC degraders of Pin1 for the treatment of acute myeloid leukemia[J]. CHEMICAL SCIENCE,2024,15(13):5027-5035.
APA Shi, Yunkai.,Liu, Minmin.,Li, Mengna.,Mao, Yiwen.,Ma, Jingkun.,...&Zhou, Bing.(2024).Discovery of potent PROTAC degraders of Pin1 for the treatment of acute myeloid leukemia.CHEMICAL SCIENCE,15(13),5027-5035.
MLA Shi, Yunkai,et al."Discovery of potent PROTAC degraders of Pin1 for the treatment of acute myeloid leukemia".CHEMICAL SCIENCE 15.13(2024):5027-5035.

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来源：上海药物研究所

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