Synthesis and structure-activity relationships of N - (3 - (1H-imidazol-2-yl) phenyl) - 3-phenylpropionamide derivatives as a novel class of covalent inhibitors of p97/VCP ATPase.

Ke Wang, Lianguo Chen, Xinyan Dai, Zi Ye, Chuan Zhou, Chong-Jing Zhang, Zhiqiang Feng

European journal of medicinal chemistry 2023 Feb 15

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Noncovalent inhibitors of p97 have entered clinical studies. Compared with noncovalent inhibitors, covalent inhibitors have unique advantages in maintaining inhibitory effect and improving the resistance of the target. We previously employed the activity-based protein profiling to definitely identify p97 as the protein target of FL-18 that has a unique scaffold of benpropargylamide coupled with an imidazole. In this study, we report a thorough structure-activity-relationship study involving the new scaffold. A total of three rounds of optimization led to the discovery of the most potent covalent inhibitor of p97 to date. A chemical proteomics study indicated that the newly-synthesized compounds still targeted the C522 residue of p97 and retained selectivity among the complicated whole proteome. This study provides a suite of new covalent inhibitors of p97 to assist in its biological study and drug discovery. Copyright © 2023 Elsevier Masson SAS. All rights reserved.

Citation

Ke Wang, Lianguo Chen, Xinyan Dai, Zi Ye, Chuan Zhou, Chong-Jing Zhang, Zhiqiang Feng. Synthesis and structure-activity relationships of N - (3 - (1H-imidazol-2-yl) phenyl) - 3-phenylpropionamide derivatives as a novel class of covalent inhibitors of p97/VCP ATPase. European journal of medicinal chemistry. 2023 Feb 15;248:115094