Structure-Based identification of a potent KDM7A inhibitor exerts anticancer activity through transcriptionally reducing MKRN1 in taxol- resistant and -sensitive triple-negative breast cancer cells

Jin-Jin Shi; Yan-Jun Liu; Zhi-Guo Liu; Ru-Yi Chen; Ran Wang; Jing Yu; Chang-Yun Li; Guan-Jun Yang; Jiong Chen

doi:10.1016/j.bioorg.2024.107945

Structure-Based identification of a potent KDM7A inhibitor exerts anticancer activity through transcriptionally reducing MKRN1 in taxol- resistant and -sensitive triple-negative breast cancer cells

Bioorg Chem. 2024 Dec:153:107945. doi: 10.1016/j.bioorg.2024.107945. Epub 2024 Nov 5.

Authors

Jin-Jin Shi¹, Yan-Jun Liu², Zhi-Guo Liu³, Ru-Yi Chen⁴, Ran Wang⁵, Jing Yu⁶, Chang-Yun Li⁷, Guan-Jun Yang⁸, Jiong Chen⁹

Affiliations

¹ State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China. Electronic address: [email protected].
² State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China. Electronic address: [email protected].
³ State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China. Electronic address: [email protected].
⁴ State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China. Electronic address: [email protected].
⁵ State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China. Electronic address: [email protected].
⁶ State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China. Electronic address: [email protected].
⁷ State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China. Electronic address: [email protected].
⁸ State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China. Electronic address: [email protected].
⁹ State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China. Electronic address: [email protected].

PMID: 39509788
DOI: 10.1016/j.bioorg.2024.107945

Abstract

KDM7A, a histone demethylase implicated in cancer proliferation, metastasis, and drug resistance, represents a crucial therapeutic target. Utilizing "mcule.com" for virtual screening of 100,000 compounds from the ZINC database, we identified 12 compounds with high affinity for KDM7A, with compound 4 emerging as the leading candidate for effectively inhibiting KDM7A's demethylase activity. Analysis of the GTRD database, the Breast Cancer Gene Expression Miner website, and recent studies highlighted MKRN1, a gene associated with cell proliferation and drug resistance, as a key intersecting factor. Compared to 2,4-pyridine dicarboxylic acid, compound 4 significantly reduced breast cancer stem cells and induced G1 phase cell cycle arrest. Mechanistically, compound 4 inhibited KDM7A's binding to H3K27me3, decreased MKRN1 transcription, and increased the levels of cell cycle regulators p16, p21, and p27, while reducing stem cell markers ALDH1A1, CD44, and CD133. These findings suggest that compound 4 could serve as a promising lead for selective KDM7A-targeting drugs. Additionally, this study is the first to demonstrate MKRN1 as a downstream gene of KDM7A, showing significant inhibitory effects in both taxol-resistant and drug-sensitive triple-negative breast cancer (TNBC) cells. This research offers new insights into the anticancer mechanisms of KDM7A inhibitors and underscores KDM7A's potential as a therapeutic target against TNBC.

Keywords: KDM7A inhibitor; MKRN1; Taxol resistance; Triple-negative breast cancer.

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation* / drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm* / drug effects
Drug Screening Assays, Antitumor*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Female
Humans
Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
Jumonji Domain-Containing Histone Demethylases / metabolism
Molecular Structure
Paclitaxel* / chemistry
Paclitaxel* / pharmacology
Structure-Activity Relationship
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / metabolism
Triple Negative Breast Neoplasms* / pathology
Ubiquitin-Protein Ligases / antagonists & inhibitors
Ubiquitin-Protein Ligases / metabolism

Substances

Antineoplastic Agents
Paclitaxel
KDM7A protein, human
Ubiquitin-Protein Ligases
Jumonji Domain-Containing Histone Demethylases
Enzyme Inhibitors