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.

LSD1-IN-7 benzenesulfonate是一种强效的可逆性赖氨酸去甲基化酶1（LSD1）抑制剂，IC₅₀值为0.25nM。LSD1-IN-7 benzenesulfonate能诱导低分化和高转移小细胞肺癌（SCLC）的细胞分化，具有有效的抗癌活性^[1]。

体外实验中，LSD1-IN-7 benzenesulfonate在THP-1细胞中靶向诱导细胞分化标志物 CD11b（EC₅₀=7nM），并在AML Kasumi-1细胞中表现出抗增殖活性（EC₅₀=2nM）。LSD1-IN-7 benzenesulfonate处理4天后，可剂量依赖性抑制胃泌素释放肽（GRP）的生成，在H209细胞中的EC₅₀值为3nM，在H1417细胞中的EC₅₀值为4nM；处理12天后，在H1417细胞中的EC₅₀值为6nM^[1]。

体内实验中，在CD-1小鼠中，单次给予5mg/kg的LSD1-IN-7 benzenesulfonate后，静脉给药表现出全身清除率为32.4mL/min·kg，消除半衰期为2小时，分布容积为7.5L/kg；口服灌胃则显示良好的吸收，AUC_0–24h为1.8μM·h，C_max为0.36μM，口服生物利用度为32%。在H1417小鼠异种移植模型中，与未治疗组相比，口服给予LSD1-IN-7 benzenesulfonate（2.5和5mg/kg/天）共4天，可剂量依赖性降低肿瘤胃泌素释放肽mRNA水平；给药65天肿瘤消退率分别为159%和178%。在患者来源的小细胞肺癌小鼠异种移植模型（SCLC PDX model）中，口服给予LSD1-IN-7 benzenesulfonate（10mg/kg/天）30天，实现了56%的肿瘤生长抑制；末次给药后15天，给药组的HE染色显示细胞结构松散、核质比降低，并出现更多凋亡小体^[1]。