Discovery of Reversible Lysine-Specific Demethylase 1 Inhibitors with Pyrazole Core for Small Cell Lung Cancer...

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Lysine-specific demethylase 1 (LSD1) is a key target for small cell lung cancer (SCLC) treatment.
• Developing selective and orally bioavailable LSD1 inhibitors is crucial for effective SCLC therapy.

Purpose of the Study:

• To design, synthesize, and evaluate novel reversible LSD1 inhibitors.
• To identify potent drug candidates for SCLC eradication with favorable pharmacokinetic profiles.

Main Methods:

• Synthesis of novel compounds featuring a carboxamido pyrazole core and a pyrrolidine-substituted phenyl ring.
• In vitro assays for LSD1 inhibition (IC50) and cancer cell growth inhibition (GI50).
• In vivo evaluation in an SCLC xenograft mouse model (NCI-H1417) to assess antitumor efficacy and pharmacokinetics.

Main Results:

• Compound 10q exhibited potent LSD1 inhibition (IC50 = 7.2 nM) and significant H1417 cell growth inhibition (GI50 = 20.0 nM).
• Compound 10q demonstrated high selectivity against homologous proteins and demethylases.
• Oral administration of compound 10q showed promising pharmacokinetics and remarkable antitumor efficacy in vivo without significant toxicity.

Conclusions:

• Compound 10q is a potent, selective, and orally bioavailable LSD1 inhibitor.
• It represents a promising therapeutic candidate for SCLC treatment, potentially in combination therapies.