Design, synthesis, and antitumor activity of NSDs inhibitors targeting lung squamous cell carcinoma

Abstract

Lung squamous cell carcinoma (LUSC), a highly aggressive subtype of lung cancer, presents significant therapeutic challenges due to its complex molecular underpinnings. Recently, NSD3 has been identified as a key driver in the pathogenesis of LUSC, providing a new direction for targeted interventions. Herein, we report the rational design, synthesis, and comprehensive biological evaluation of a series of NSD3 inhibitors, culminating in the identification of compound A8, which demonstrates potent inhibitory activity against NSD3 and LUSC cell proliferation, with an IC₅₀ of 0.355 μM in NCI–H1703 cells, and less toxicity to non-cancerous HEK293T cells. Cellular thermal shift assays confirmed the binding affinity of compound A8 for NSD3, promoting protein stabilization. Mechanistic investigations revealed that compound A8 induces apoptosis in LUSC cells in a dose-dependent manner and exhibits significant antitumor effects in both in vitro and in vivo models. Notably, compound A8 displayed favorable pharmacokinetic properties and efficaciously suppressed tumor growth in an NCI–H520 xenograft mouse model without observable adverse effects. These findings collectively establish compound A8 as a promising candidate for the development of targeted therapies against LUSC, highlighting the therapeutic potential of NSD3 inhibition.