Perspectives and challenges in developing small molecules targeting purine nucleoside phosphorylase

Yangyang Chen; Yang Li; Jing Gao; Quanwei Yu; Yiwen Zhang; Jifa Zhang

doi:10.1016/j.ejmech.2024.116437

Perspectives and challenges in developing small molecules targeting purine nucleoside phosphorylase

Eur J Med Chem. 2024 May 5:271:116437. doi: 10.1016/j.ejmech.2024.116437. Epub 2024 Apr 20.

Authors

Yangyang Chen¹, Yang Li¹, Jing Gao¹, Quanwei Yu², Yiwen Zhang³, Jifa Zhang⁴

Affiliations

¹ Department of Neurology, Laboratory of Neuro-system and Multimorbidity and State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
² Department of Neurology, Laboratory of Neuro-system and Multimorbidity and State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: yqw@stu.scu.edu.cn.
³ Department of Neurology, Laboratory of Neuro-system and Multimorbidity and State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: yiwenzhang@scu.edu.cn.
⁴ Department of Neurology, Laboratory of Neuro-system and Multimorbidity and State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: zjf298257@163.com.

PMID: 38701712
DOI: 10.1016/j.ejmech.2024.116437

Abstract

As a cytosolic enzyme involved in the purine salvage pathway metabolism, purine nucleoside phosphorylase (PNP) plays an important role in a variety of cellular functions but also in immune system, including cell growth, apoptosis and cancer development and progression. Based on its T-cell targeting profile, PNP is a potential target for the treatment of some malignant T-cell proliferative cancers including lymphoma and leukemia, and some specific immunological diseases. Numerous small-molecule PNP inhibitors have been developed so far. However, only Peldesine, Forodesine and Ulodesine have entered clinical trials and exhibited some potential for the treatment of T-cell leukemia and gout. The most recent direction in PNP inhibitor development has been focused on PNP small-molecule inhibitors with better potency, selectivity, and pharmacokinetic property. In this perspective, considering the structure, biological functions, and disease relevance of PNP, we highlight the recent research progress in PNP small-molecule inhibitor development and discuss prospective strategies for designing additional PNP therapeutic agents.

Keywords: Cancer; Drug design; Immunological disease; PNPIs; Structure-activity relationships.

Publication types

Review

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Drug Development
Enzyme Inhibitors* / chemical synthesis
Enzyme Inhibitors* / chemistry
Enzyme Inhibitors* / pharmacology
Humans
Molecular Structure
Purine-Nucleoside Phosphorylase* / antagonists & inhibitors
Purine-Nucleoside Phosphorylase* / metabolism
Small Molecule Libraries* / chemistry
Small Molecule Libraries* / pharmacology
Structure-Activity Relationship

Substances

Purine-Nucleoside Phosphorylase
Enzyme Inhibitors
Small Molecule Libraries
Antineoplastic Agents