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

doi:10.1016/j.ejmech.2023.115094

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

Eur J Med Chem. 2023 Feb 15:248:115094. doi: 10.1016/j.ejmech.2023.115094. Epub 2023 Jan 6.

Authors

Ke Wang¹, Lianguo Chen², Xinyan Dai¹, Zi Ye³, Chuan Zhou¹, Chong-Jing Zhang⁴, Zhiqiang Feng⁵

Affiliations

¹ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xiannongtan Street, Beijing, 100050, PR China.
² The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, PR China.
³ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xiannongtan Street, Beijing, 100050, PR China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China.
⁴ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xiannongtan Street, Beijing, 100050, PR China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China. Electronic address: zhangchongjing@imm.ac.cn.
⁵ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xiannongtan Street, Beijing, 100050, PR China. Electronic address: fengzhq@imm.ac.cn.

PMID: 36634454
DOI: 10.1016/j.ejmech.2023.115094

Abstract

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.

Keywords: ATPase activity; Covalent inhibitor; Cytotoxicity; P97; Synthesis.

MeSH terms

Adenosine Triphosphatases
Enzyme Inhibitors* / chemistry
Imidazoles* / pharmacology
Protein Binding
Structure-Activity Relationship

Substances

Adenosine Triphosphatases
Enzyme Inhibitors
Imidazoles
p97 inhibitor fl-18