Work

Discovery and biological evaluation of a novel and highly potent JAK2 inhibitor for the treatment of triple negative breast cancer

Year: 2025

Type: article

Abstract: Janus kinase 2 (JAK2) is considered an attractive target for the treatment of triple-negative breast cancer (TNBC). Herein, we discovered six JAK2 inhibitors using structure-based virtual screening and molecular docking. Among them, JNN-5 was the best compound. It indicated strong inhibitory effects on JAK2 in the nanomolar range (IC50 = 0.41 ± 0.03 nM), and high selectivity for JAK2 over JAK1 and JAK3 (selectivity index (SI) > 73.17). Moreover, molecular dynamics (MD) simulation exhibited that JNN-5 bound with high stability to JAK2 JH1. Cellular assays revealed that JNN-5 displayed strong antiproliferative activities in the TNBC cell lines (MDA-MB-468, MDA-MB-213, HCC70, MDA-MB-157). JNN-5 significantly reduced the migration of HUVECs with the dose-dependence. JNN-5 had a significant inhibitory effect on multidrug-resistant MDA-MB-231/ADR (IC50 = 0.37 ± 0.02 μM). These data demonstrate that JNN-5 may be a highly effective and selective antitumor compound for the treatment of TNBC.

Source: Journal of Enzyme Inhibition and Medicinal Chemistry

DOI: 10.1080/14756366.2025.2488127

Authors: Yingxiang Miao, Shudan Yang, Fang Zhang, Jindong Li, Yan Zhang

Institutions: Nantong University, China Pharmaceutical University, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University

Language: English

Topic: Computational Drug Discovery Methods

Subfield: Computational Theory and Mathematics

Field: Computer Science

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,306