Structure-activity characteristics and safety signal analysis of thrombopoietin receptor agonists

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Author: YAN Qianci ^1, ² SHANG Nan ¹ YUE Xiunan ³ CHEN Wanying ³  ZHENG Xiaojun ¹

Affiliation: 1. Department of Pharmacy, First Hospital of Shanxi Medical University, Taiyuan 030001, China 2. School of Medical Sciences, Shanxi Medical University, Taiyuan 030001, China 3. School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China

Keywords: Thrombopoietin receptor agonists Immune thrombocytopenia Quantitative structure-activity relationship Network pharmacology Pharmacovigilance

DOI: 10.12173/j.issn.1005-0698.202601013

Reference: YAN Qianci, SHANG Nan, YUE Xiunan, CHEN Wanying, ZHENG Xiaojun. Structure-activity characteristics and safety signal analysis of thrombopoietin receptor agonists[J]. Yaowu Liuxingbingxue Zazhi, 2026, 35(4): 398-408. DOI: 10.12173/j.issn.1005-0698.202601013.[Article in Chinese]  Copied

Abstract
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Abstract

Objective To investigate the potential association between molecular structural features and clinical safety differences among thrombopoietin receptor agonists (TPO-RAs).

Methods An integrated analytical strategy was employed. Small-molecule compounds targeting the thrombopoietin receptor (MPL), including eltrombopag, were retrieved from the ChEMBL database to construct a quantitative structure–activity relationship (QSAR) model for identifying key structural features associated with biological activity. Based on these features, a comparative analysis of molecular descriptors was subsequently performed across 4 commonly used small-molecule TPO-RAs in clinical practice, including eltrombopag, avatrombopag, lusutrombopag, and hetrombopag. A protein–protein interaction (PPI) network of MPL was constructexd using the STRING database, followed by functional enrichment analyses to elucidate the downstream signaling pathways potentially affected by activation of the common targets of TPO-RAs, thereby providing a systems biology framework for interpreting differences in safety profiles among these agents. Adverse drug event (ADE) reports for TPO-RAs in patients with immune thrombocytopenia (ITP) were extracted from the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2008 to the fourth quarter of 2024. Signal detection was performed using the reporting odds ratio (ROR) method and Bayesian confidence propagation neural network (BCPNN) method, followed by age-stratified subgroup analysis.

Results QSAR analysis indicated that molecular size, topological complexity, and electronic properties were key structural determinants of MPL activation, with clinically used TPO-RAs exhibiting differences across these parameters. Network pharmacology analysis further demonstrated that MPL-associated proteins were significantly enriched in the JAK/STAT signaling pathway as well as hematopoiesis-and immune-related pathways, providing a pathway-level context for the potential downstream effects arising from these differences. Pharmacovigilance analysis based on the FAERS database identified drug-specific signal patterns and age-related differences for ADEs such as hepatotoxicity, thrombosis, and gastrointestinal events among different TPO-RAs.

Conclusion By integrating QSAR, network pharmacology, and pharmacovigilance data, this study preliminarily established a “structure-target-safety” analytical framework for TPO-RAs, suggesting that molecular structural differences may underlie the clinical safety heterogeneity of this drug class, providing a reference for further mechanistic studies and clinical risk monitoring.

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