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

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Lung squamous cell carcinoma (LUSC) is an aggressive cancer with limited targeted therapies.
• NSD3 has emerged as a critical molecular driver in LUSC pathogenesis.
• Targeting NSD3 presents a novel therapeutic strategy for LUSC.

Purpose of the Study:

• To design, synthesize, and evaluate novel NSD3 inhibitors for LUSC treatment.
• To identify a potent and selective NSD3 inhibitor with therapeutic potential.
• To investigate the mechanism of action and preclinical efficacy of lead compounds.

Main Methods:

• Rational drug design and chemical synthesis of NSD3 inhibitors.
• In vitro evaluation of inhibitory activity against NSD3 and LUSC cell lines (e.g., NCI-H1703).
• Cellular thermal shift assays (CETSA) to confirm target engagement.
• In vivo efficacy studies using xenograft mouse models (e.g., NCI-H520).
• Pharmacokinetic and toxicity assessments.

Main Results:

• Compound A8 demonstrated potent inhibition of NSD3 with an IC50 of 0.355 μM in NCI-H1703 cells.
• A8 showed selective toxicity, with reduced effects on non-cancerous HEK293T cells.
• CETSA confirmed A8 binds and stabilizes NSD3.
• Mechanistic studies showed A8 induces apoptosis and exhibits dose-dependent antitumor effects.
• A8 displayed favorable pharmacokinetics and suppressed tumor growth in vivo without adverse effects.

Conclusions:

• Compound A8 is a highly promising NSD3 inhibitor for LUSC therapy.
• Targeting NSD3 with compound A8 offers a viable strategy for LUSC treatment.
• A8 warrants further clinical investigation for LUSC patients.