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
Ubiquitin specific peptidase 28(USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date,only fe...Ubiquitin specific peptidase 28(USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date,only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound 19 potently inhibited USP28(IC50=1.10 ± 0.02 μmol/L, Kd=40 nmol/L), showing selectivity over USP7 and LSD1(IC50> 100 μmol/L). Compound 19 was cellularly engaged to USP28 in gastric cancer cells. Compound 19 reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition(EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound 19. Collectively, compound 19 could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deubiquitinase in cancers.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.
基金supported by the National Key Research Program of Proteins(No.2016YFA0501800 for Hongmin Liu,China)National Natural Science Foundation of China(Nos.81430085 and 81773562 for Hongmin Liu and Nos.81703326 and 81973177 for Bin Yu)+2 种基金Scientific Program of Henan Province(No.19A350012 for Xiaojing Shi,China)China Postdoctoral Science Foundation(No.2018M630840 and 2019T120641 for Bin Yu)the Henan Scientific Innovation Talent Team,Department for Education(No.19ITSTHN001 for Wen Zhao,China)
文摘Ubiquitin specific peptidase 28(USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date,only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound 19 potently inhibited USP28(IC50=1.10 ± 0.02 μmol/L, Kd=40 nmol/L), showing selectivity over USP7 and LSD1(IC50> 100 μmol/L). Compound 19 was cellularly engaged to USP28 in gastric cancer cells. Compound 19 reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition(EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound 19. Collectively, compound 19 could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deubiquitinase in cancers.