N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure-activity relationships and X-ray crystallographic studies

Minglei Li; Shengjie Liu; Hui Chen; Xinyu Zhou; Jin Zhou; Shuxi Zhou; Haoliang Yuan; Qing-Long Xu; Jun Liu; Keguang Cheng; Hongbin Sun; Yue Wang; Caiping Chen; Xiaoan Wen

doi:10.1016/j.ejmech.2020.112279

N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure-activity relationships and X-ray crystallographic studies

Eur J Med Chem. 2020 Aug 1:199:112279. doi: 10.1016/j.ejmech.2020.112279. Epub 2020 May 5.

Authors

Minglei Li¹, Shengjie Liu¹, Hui Chen¹, Xinyu Zhou¹, Jin Zhou¹, Shuxi Zhou¹, Haoliang Yuan¹, Qing-Long Xu¹, Jun Liu¹, Keguang Cheng², Hongbin Sun¹, Yue Wang³, Caiping Chen⁴, Xiaoan Wen⁵

Affiliations

¹ Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
² State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy of Guangxi Normal University, Guilin, 541004, China.
³ School of Science, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: zwy_1115@cpu.edu.cn.
⁴ Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: caiping.chen@cpu.edu.cn.
⁵ Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: wxagj@cpu.edu.cn.

PMID: 32497973
DOI: 10.1016/j.ejmech.2020.112279

Abstract

USP7 as a deubiquitinase plays important roles in regulating the stability of some oncoproteins including MDM2 and DNMT1, and thus represents a potential anticancer target. Through comparative analysis of USP7 co-crystal structures in complex with the reported piperidinol inhibitors, we noticed that the USP7 Phe409 sub-site might have good adaptability to the ligands. Based on this observation, 55 N-aromatic and N-benzyl piperidinol derivatives were designed, synthesized and biologically evaluated, among which compound L55 was identified as a highly selective and potent USP7 inhibitor (IC₅₀ = 40.8 nM, K_D = 78.3 nM). X-ray crystallographic studies revealed that L55 bound to USP7 with a new pose that was very different from the previously reported inhibitors. The results of cellular assays showed that L55 had strong antitumor activity against LNCaP (IC₅₀ = 29.6 nM) and RS4; 11 (IC₅₀ = 41.6 nM) cells, probably through inducing cell death and restricting G0/G1 and S phases. Moreover, L55 dose-dependently reduced the protein levels of MDM2 and DNMT1 and increased the protein levels of p53 and p21. These findings could have valuable implications for designing novel structural classes of USP7 inhibitors.

Keywords: Crystallographic study; Deubiquitinase; Piperidine; Structure-activity relationship; USP7.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Models, Molecular
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Structure-Activity Relationship
Ubiquitin-Specific Peptidase 7 / antagonists & inhibitors*
Ubiquitin-Specific Peptidase 7 / metabolism

Substances

Antineoplastic Agents
Enzyme Inhibitors
Piperidines
1-benzylpiperidine
USP7 protein, human
Ubiquitin-Specific Peptidase 7