Small molecules targeting Pin1 as potent anticancer drugs

Jing Zhang; Wenwen Zhou; Yunyu Chen; Yanchang Wang; Zongru Guo; Wenhui Hu; Yan Li; Xiaomin Han; Shuyi Si

doi:10.3389/fphar.2023.1073037

Small molecules targeting Pin1 as potent anticancer drugs

Front Pharmacol. 2023 Mar 27:14:1073037. doi: 10.3389/fphar.2023.1073037. eCollection 2023.

Authors

Jing Zhang¹, Wenwen Zhou¹, Yunyu Chen², Yanchang Wang³, Zongru Guo⁴, Wenhui Hu⁵, Yan Li¹, Xiaomin Han⁶, Shuyi Si¹

Affiliations

¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Institute for Drug Screening and Evaluation, Wannan Medical College, Wuhu, China.
³ Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United States.
⁴ Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁵ Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, The Fifth Affiliated Hospital, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China.
⁶ China National Center for Food Safety Risk Assessment, Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.

Abstract

Background: Pin1 is a member of the evolutionarily conserved peptidyl-prolyl isomerase (PPIase) family of proteins. Following phosphorylation, Pin1-catalyzed prolyl-isomerization induces conformational changes, which serve to regulate the function of many phosphorylated proteins that play important roles during oncogenesis. Thus, the inhibition of Pin1 provides a unique means of disrupting oncogenic pathways and therefore represents an appealing target for novel anticancer therapies. Methods: As Pin1 is conserved between yeast and humans, we employed budding yeast to establish a high-throughput screening method for the primary screening of Pin1 inhibitors. This effort culminated in the identification of the compounds HWH8-33 and HWH8-36. Multifaceted approaches were taken to determine the inhibition profiles of these compounds against Pin1 activity in vitro and in vivo, including an isomerization assay, surface plasmon resonance (SPR) technology, virtual docking, MTT proliferation assay, western blotting, cell cycle analysis, apoptosis analysis, immunofluorescence analysis, wound healing, migration assay, and nude mouse assay. Results: In vitro, HWH8-33 and HWH8-36 could bind to purified Pin1 and inhibited its enzyme activity; showed inhibitory effects on cancer cell proliferation; led to G2/M phase arrest, dysregulated downstream protein expression, and apoptosis; and suppressed cancer cell migration. In vivo, HWH8-33 suppressed tumor growth in the xenograft mice after oral administration for 4 weeks, with no noticeable toxicity. Together, these results show the anticancer activity of HWH8-33 and HWH8-36 against Pin1 for the first time. Conclusion: In summary, we identified two hit compounds HWH8-33 and HWH8-36, which after further structure optimization have the potential to be developed as antitumor drugs.

Keywords: Pin1; anticancer; high-throughput screening; prolyl-isomerization; small molecular inhibitors.

Grants and funding

This work was supported by National Natural Science Foundation of China (No. 81370087, 81703546) and CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-1-054).