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. ...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 8 a(IC50=3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15 u(IC50=49 nmol/L, and Ki= 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3 K4 me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency ofcompound 15 u. Compound 15 u 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, 15 u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15 u induced expression of CD86 and CD11 b 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 triazolefused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1 A inhibitors.展开更多
Epithelial-mesenchymal transition (EMT) is a plastic and reversible process, essential for development and tissue homeostasis. Under pathological conditions, EMT causes induction of tumor growth, angiogenesis and meta...Epithelial-mesenchymal transition (EMT) is a plastic and reversible process, essential for development and tissue homeostasis. Under pathological conditions, EMT causes induction of tumor growth, angiogenesis and metastasis. According to its reversible nature, the EMT program is associated with vast epigenetic changes. Targeting the epigenetic network that controls the EMT pathway in disease progression is a novel promising strategy to fight cancer metastasis. The impact of alterations in histone methylation in cancer has led to the identification of histone methyltransferases and demethylases as promising novel targets for therapy. Specifically, the lysine specific demethylase 1 (LSD1, also known as KDM1A) plays a pivotal role in the regulation of EMT. Here we present an overview of the causative role of LSD1 in the EMT process, summarizing recent findings on its emerging functions in cell migration and invasion in breast cancer.展开更多
基金supported by the National Key Research Program of Proteins(Nos.2016YFA0501800 and 2017YFD0501401,China)the National Natural Science Foundation of China(Nos.81703326,81773562,81430085 and 21403200,China)+5 种基金the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nan-jing University,China(No.KF-GN-201902,China)Outstanding Young Talent Research Fund of Zhengzhou University(No.1521331002,China)Scientific Program of Henan Province(Nos.182102310123 and 161100310100,China)China Postdoctoral Science Foundation(No.2018M630840,China)Key Research Program of Higher Education of Henan Province(Nos.15A350018 and 18B350009,China)the Starting Grant of Zhengzhou University(No.32210533,China)
文摘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 8 a(IC50=3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15 u(IC50=49 nmol/L, and Ki= 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3 K4 me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency ofcompound 15 u. Compound 15 u 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, 15 u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15 u induced expression of CD86 and CD11 b 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 triazolefused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1 A inhibitors.
文摘目的研究LSD1与冬凌草提取物的相互作用。方法在PH 7.40的缓冲液中,采用循环伏安法研究LSD1与冬凌草提取物(JD160和JD284)在不同条件下的相互作用。结果在分别改变提取物浓度和扫描速率的条件下,提取物峰电流与提取物浓度和扫描速率均呈现良好的线性关系。在p H 7.40的缓冲液中,LSD1无峰电流出现,提取物有峰电流出现,且其电化学行为具有典型的不可逆特征。当LSD1逐渐加入到提取物中,二者发生作用,峰电流减小,峰电位负移。结论 JD160和JD284均可与LSD1结合生成非电活性化合物,使电解液中游离化合物浓度降低。LSD1的加入使冬凌草提取物的氧化峰峰值电流减小。LSD1与JD160的相互作用可逆,与JD284不可逆。
文摘Epithelial-mesenchymal transition (EMT) is a plastic and reversible process, essential for development and tissue homeostasis. Under pathological conditions, EMT causes induction of tumor growth, angiogenesis and metastasis. According to its reversible nature, the EMT program is associated with vast epigenetic changes. Targeting the epigenetic network that controls the EMT pathway in disease progression is a novel promising strategy to fight cancer metastasis. The impact of alterations in histone methylation in cancer has led to the identification of histone methyltransferases and demethylases as promising novel targets for therapy. Specifically, the lysine specific demethylase 1 (LSD1, also known as KDM1A) plays a pivotal role in the regulation of EMT. Here we present an overview of the causative role of LSD1 in the EMT process, summarizing recent findings on its emerging functions in cell migration and invasion in breast cancer.