LSD1-IN-7 benzenesulfonate (Synonyms: CC-90011 benzenesulfonate; LSD1-IN-7 benzenesulfonate)

LSD1-IN-7 benzenesulfonate is a potent reversible inhibitor of lysine demethylase-1 (LSD1) with an IC₅₀ of 0.25nM. LSD1-IN-7 benzenesulfonate induces differentiation of poorly differentiated, highly metastatic small cell lung cancer (SCLC) cells and exhibits potent anticancer activity^[1].

In vitro, LSD1-IN-7 benzenesulfonate induces on-target cellular differentiation marker CD11b in THP-1 cells (EC₅₀=7nM) and exhibits antiproliferative activity in AML Kasumi-1 cells (EC₅₀=2nM). LSD1-IN-7 benzenesulfonate inhibited gastrin-releasing peptide (GRP) in a dose-dependent manner after 4 days of treatment, with an EC₅₀ of 3nM in H209 cells and 4nM in H1417 cells; after 12 days, the EC₅₀ in H1417 cells was 6nM^[1].

In vivo, in CD-1 mice, a single 5mg/kg dose of LSD1-IN-7 benzenesulfonate showed a systemic clearance of 32.4mL/min·kg, an elimination half-life of 2h, and a volume of distribution of 7.5L/kg after intravenous administration, while oral gavage resulted in good absorption with an AUC_0–24h of 1.8μM·h, a C_max of 0.36μM, and an oral bioavailability of 32%. In the H1417 xenograft mice model, compared with the untreated group, oral administration of LSD1-IN-7 benzenesulfonate at (2.5 and 5mg/kg/d) for 4 days dose-dependently reduced tumor GRP mRNA levels, while 65 days of treatment induced tumor regression of 159% and 178%, respectively. In the SCLC PDX (Patient-Derived Xenograft) mice model, oral administration of LSD1-IN-7 benzenesulfonate at 10mg/kg/d for 30 days achieved 56% tumor growth inhibition; 15 days after the last dose, H&E staining in the treated group showed a loose cellular structure, a reduced nuclear-to-cytoplasmic ratio, and increased apoptotic bodies^[1].

References:
[1] Kanouni T, Severin C, Cho RW, et al. Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1). J Med Chem. 2020;63(23):14522-14529.