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

Abstract

Selective lysine-specific demethylase 1 (LSD1) inhibition has emerged as a robust strategy for small cell lung cancer (SCLC) eradication. Herein, we describe the structural design, synthesis, and biological evaluation of novel reversible LSD1 inhibitors containing a carboxamido pyrazole core with a pyrrolidine-substituted phenyl ring. Notably, compound 10q demonstrated potent LSD1 inhibition with an IC50 value of 7.2 nM and effective H1417 cell growth inhibition with a GI50 value of 20.0 nM. Moreover, it showed notable selectivity against homologous proteins and demethylases. The oral administration of compound 10q demonstrated encouraging pharmacokinetic profiles and remarkable antitumor efficacy in the NCI-H1417 SCLC xenograft model using NOD/Shi-scid/IL-2Rγnull mice without notable toxicity. Furthermore, the potential of compound 10q is proposed by combinatorial therapy with chemotherapeutic agents for treating SCLC. Therefore, compound 10q can be considered a promising candidate as a selective and orally bioavailable LSD1 inhibitor.