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Abstract：
Histone lysine specific demethylase 1 (LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8a (IC50 = 3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15u (IC50 = 49 nmol/L, and K i = 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3K4me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency of compound 15u. Compound 15u also showed strong antiproliferative activity against four leukemia cell lines (OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15u induced expression of CD86 and CD11b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation. The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazole-fused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1A inhibitors.
摘要：
组蛋白赖氨酸特异性脱甲基酶1(LSD1)已被认为是表观遗传学翻译后过程中的重要调节剂。LSD1的失调与各种癌症的发展有关。在这里，我们报道了发现化合物8a（IC50=3.93μmol/L）和进一步的药物化学努力，导致化合物15u的产生（IC50=49nmol/L，且Ki=16nmol/L)，与H3K4me2可逆地和竞争性地抑制LSD1，并且相对于MAO-A/B对LSD1具有选择性。进行对接研究以合理化化合物15u的效力。化合物15u还对四种白血病细胞系（OCL-AML3，K562，THP-1和U937）以及淋巴瘤细胞系Raji显示出强的抗增殖活性，IC50值为1.79、1.30、0.45、1.22和1.40μmol/L。分别。在THP-1细胞系中,15u显著抑制集落形成并引起显著的形态变化。化合物15u诱导THP-1细胞中CD86和CD11b的表达,证实其细胞活性和诱导分化的能力。研究结果进一步表明，靶向LSD1是一种有前途的AML治疗策略。三唑-稠合嘧啶衍生物是开发LSD1/KDM1A抑制剂的新支架。
