Background:Protein Interacting with NIMA1 (PIN1) is a distinct enzyme, known as a peptidyl-prolyl cis-trans isomerase (PPIase), which catalyzes the cis-trans isomerization of amide bonds in proteins containing phosphoserine/threonine-proline (pSer/Thr-Pro) motifs, presenting a unique therapeutic opportunity for addressing multiple disorders.Methods:A series of 140 thiazole compounds were created using the shape similarity technique with the intention of discovering effective PIN1 inhibitors with a new scaffold. The designed compounds were docked into the enzyme's ATP binding site, and the binding free energies for all docked conformations were calculated. The compounds were evaluated for their ADMET and drug-likeness properties. Following the identification of top candidates, molecular dynamics simulations were conducted to investigate the binding dynamics of the highest-scoring compound.Results:Based on computational findings, sixteen compounds were identified as potential PIN1 inhibitors. Among the sixteen compounds, four (S8Ba, S8Bb, S8Bd, and S8Bd) exhibited the most favorable ADMET profiles and robust interactions with key PIN1 residues. Molecular dynamics simulations confirmed that S8Ba and S8Bd exhibited the most promising activity over 100ns.Conclusion:The results corroborated the docking outcomes, validating the selected hits as potential PIN1 inhibitors. This breakthrough could influence the development of therapeutic leads for combating diabetes, cancer, and Alzheimer's disease.

13 Feb 2025·Journal of Medicinal Chemistry

Structure-Guided Optimization and Preclinical Evaluation of 6-O-Benzylguanine-Based Pin1 Inhibitor for Hepatocellular Carcinoma Treatment

Article

Author: Zhou, Jian-Kang ; Zheng, Qingquan ; Gong, Yanqiu ; Luo, Yao ; Ai, Min ; Ye, Zixia ; Ming, Yue ; Peng, Yong ; Li, Jiao ; Shen, Xianyan ; Liu, Xuesha ; Zheng, Yuanyuan ; Zhao, Yun ; He, Juan ; Pu, Wenchen ; Fan, Xin ; Wei, Rong ; Wang, Chun ; Guo, Yingli

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths globally, and the need for effective systemic therapies for HCC is urgent. Our previous work reveals that Pin1 is a potential anti-HCC target, which regulates miRNA biogenesis and identifies API-1 as a novel Pin1 inhibitor to suppresses HCC. However, a great demand in HCC therapy as well as the limited chemical stability and pharmacokinetic feature of API-1 motivated us to find improved Pin1 inhibitors. Herein, we designed and synthesized diverse 6-O-benzylguanine derivatives and discovered API-32 as a novel Pin1 inhibitor with better stability and pharmacokinetic property over API-1. API-32 directly interacted with the Pin1 PPIase domain to inhibit Pin1 activity. API-32 significantly suppressed the cell proliferation and migration of HCC cells by blocking Pin1's downstream signal. Moreover, API-32 exhibited an enhanced inhibitory function against the HCC tumor in mice models without obvious toxicity, making it a promising drug candidate for HCC treatment.

09 Jan 2025·ACS Medicinal Chemistry Letters

Discovery of Novel Pyrimidine Derivatives as Human Pin1 Covalent Inhibitors

Article

Author: Zhou, Jie ; Wang, Xiaoyu ; Tang, Guodong ; Jin, Jing ; Cui, Guonan ; Xu, Bailing ; Tian, Meizhen

Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) is a unique peptidyl-prolyl isomerase (PPIase), and inactivation of Pin1 with a covalent inhibitor is a potential strategy for developing anticancer agents. Herein, a series of sulfolane amino-substituted 2-chloro-5-nitropyrimidine derivatives were disclosed as structurally distinct covalent inhibitors toward Pin1, which were validated for their covalent binding to Cys113 of Pin1 by X-ray cocrystal structures of compounds 4a (IC₅₀ = 11.55 μM) and 6a (IC₅₀ = 3.15 μM). This work provided a new approach for covalent inhibition of Pin1 by taking advantage of the 2-chloro-5-nitropyrimidine as the electrophilic warhead, which might benefit the discovery of potent and drug-like Pin1 inhibitors.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	The Ohio State University	24 Feb 2010

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