Identification of a novel heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) ligand that disrupts HnRNPA2B1/nucleic acid interactions to inhibit the MDMX-p53 axis in gastric cancer

Lei Hu; Shuqi Liu; Hongying Yao; Yuemiao Hu; Yingjie Wang; Jingpeng Jiang; Xiaopeng Li; Fenghua Fu; Qikun Yin; Hongbo Wang

doi:10.1016/j.phrs.2023.106696

Identification of a novel heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) ligand that disrupts HnRNPA2B1/nucleic acid interactions to inhibit the MDMX-p53 axis in gastric cancer

Pharmacol Res. 2023 Mar:189:106696. doi: 10.1016/j.phrs.2023.106696. Epub 2023 Feb 13.

Authors

Lei Hu¹, Shuqi Liu¹, Hongying Yao¹, Yuemiao Hu², Yingjie Wang¹, Jingpeng Jiang¹, Xiaopeng Li¹, Fenghua Fu¹, Qikun Yin³, Hongbo Wang⁴

Affiliations

¹ School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
² School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
³ School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China. Electronic address: qkyin@ytu.edu.cn.
⁴ School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China. Electronic address: hongbowang@ytu.edu.cn.

PMID: 36791898
DOI: 10.1016/j.phrs.2023.106696

Abstract

Gastric carcinoma is a highly malignant tumor that still lacks effective molecular targets. Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an essential oncogenic driver overexpressed in various cancers. The potential role of hnRNPA2B1 in oncotherapy has not been revealed because of the absence of active chemical molecules. In this study, we identified the pseudourea derivative XI-011 as a novel hnRNPA2B1 ligand using chemical proteomics. An interaction study indicated that XI-011 could bind the nucleotide-binding domain to disrupt the recruitment of hnRNPA2B1 to the promoter and untranslated region of the murine double minute X (MDMX) gene, thereby inhibiting its transcription. In addition, chemical targeting of hnRNPA2B1 recovered inactivated p53 and enhanced the therapeutic efficacy of apatinib in vivo. This work presented a novel strategy to restore p53 activity for the treatment of gastric cancers via chemically targeting hnRNPA2B1.

Keywords: Anti-gastric cancer; Biotin (PubChem CID: 171548); HnRNPA2B1; MDMX transcription inhibition; P53 reactivation; XI-011 (PubChem CID: 16759161); apatinib (PubChem CID: 11315474).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Heterogeneous-Nuclear Ribonucleoproteins
Humans
Ligands
Mice
Proto-Oncogene Proteins c-mdm2 / metabolism
Stomach Neoplasms*
Tumor Suppressor Protein p53*

Substances

(10-methyl-9-anthryl)methyl imidothiocarbamate
Tumor Suppressor Protein p53
Ligands
Heterogeneous-Nuclear Ribonucleoproteins
Proto-Oncogene Proteins c-mdm2