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共15篇 平均IF=5.5 (2.2-10.1)更多分析
  • 2区Q1影响因子: 5.5
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    1. SKLB1206, a novel orally available multikinase inhibitor targeting EGFR activating and T790M mutants, ErbB2, ErbB4, and VEGFR2, displays potent antitumor activity both in vitro and in vivo.
    作者:Pan Youli , Xu Yong , Feng Shan , Luo Shidong , Zheng Renlin , Yang Jiao , Wang Lijiao , Zhong Lei , Yang Han-Yu , Wang Bing-Lin , Yu Yang , Liu Jingjing , Cao Zhixing , Wang Xiaoyan , Ji Pan , Wang Zerong , Chen Xin , Zhang Shuang , Wei Yu-Quan , Yang Sheng-Yong
    期刊:Molecular cancer therapeutics
    日期:2012-02-08
    DOI :10.1158/1535-7163.MCT-11-0679
    Anti-epidermal growth factor receptor (EGFR) treatment has been successfully applied in clinical cancer therapy. However, the clinical efficacy of first-generation reversible EGFR inhibitors, such as gefitinib and erlotinib, is limited by the development of drug-resistant mutations, including the gatekeeper T790M mutation and upregulation of alternative signaling pathways. Second-generation irreversible EGFR inhibitors that were designed to overcome the drug resistance due to the T790M mutation have thus far had limited success. Here, we report a novel reversible EGFR inhibitor, SKLB1206, which has potent activity against EGFR with gefitinib-sensitive and -resistant (T790M) mutations. In addition, SKLB1206 has also considerable inhibition potency against some other related oncokinases, including ErbB2, ErbB4, and VEGF receptor 2 (VEGFR2). SKLB1206 exhibited highly antiproliferative activity against a range of EGFR-mutant cell lines, including gefitinib-sensitive and -resistant cell lines, and EGFR or ErbB2-overexpressing cell lines. SKLB1206 also showed a potent antiangiogenesis effect in vitro, in a zebrafish embryonic angiogenesis assay, and in an alginate-encapsulate tumor cell assay. In vivo, oral administration of SKLB1206 showed complete tumor regression in gefitinib-sensitive HCC827 and PC-9 xenograft models and showed a considerable antitumor effect on the gefitinib-resistant H1975 model as well as other EGFR/ErbB2-overexpressing or -dependent tumor models including A431, LoVo, and N87 established in athymic mice. SKLB1206 also showed a very good oral bioavailability (50.1%). Collectively, these preclinical evaluations may support clinical development of SKLB1206 for cancers with EGFR-activating/resistance mutations or EGFR/ErbB2 overexpressed.
  • 2区Q1影响因子: 5.5
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    2. A preclinical evaluation of SKLB261, a multikinase inhibitor of EGFR/Src/VEGFR2, as a therapeutic agent against pancreatic cancer.
    作者:Pan Youli , Zheng Mingwu , Zhong Lei , Yang Jiao , Zhou Shu , Qin Ya , Xiang Rong , Chen Yuzong , Yang Sheng-Yong
    期刊:Molecular cancer therapeutics
    日期:2014-12-17
    DOI :10.1158/1535-7163.MCT-14-0485
    The clinical prognosis of pancreatic cancer remains rather disappointing despite tremendous efforts in exploring medical treatments in the past two decades. Development of more effective treatment strategies is still desperately needed to improve outcomes in patients with pancreatic cancer. SKLB261 is a multikinase inhibitor obtained recently through a lead optimization. In this investigation, we shall evaluate its anti-pancreatic cancer effects both in vitro and in vivo. SKLB261 is a multikinase inhibitor potently inhibiting EGFR, Src, and VEGFR2 kinases. It could significantly inhibit cell proliferation, migration, and invasion, and induce apoptosis in cellular assays of human pancreatic cancer cells that are sensitive or resistant to dasatinib and/or gemcitabine. Western blot analysis showed that SKLB261 inhibited the activation of EGFR and Src kinases as well as their downstream signaling proteins, including FAK, ERK, and STAT3. SKLB261 also showed potent antiangiogenic effects in transgenic zebrafish models. In vivo, SKLB261 displayed more potent antitumor activities than dasatinib, gemcitabine, or erlotinib in pancreatic cancer xenografts, including BxPC-3, PANC-1, AsPC-1, and HPAC. Furthermore, mice receiving SKLB261 therapy showed significant survival advantage compared with vehicle-treated and gemcitabine-treated groups in an experimental metastasis model of pancreatic cancer. These data, together with the good pharmacokinetic properties and low toxicity of this compound, provide a rationale for the ongoing clinical evaluation of SKLB261 in the treatment of pancreatic cancer.
  • 3区Q2影响因子: 4.6
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    3. Discovery of 12O-A Novel Oral Multi-Kinase Inhibitor for the Treatment of Solid Tumor.
    作者:Fan Yan , Huang Zhi , Wang Xiaoshuang , Ma Yakun , Li Yongtao , Yang Shengyong , Shi Yi
    期刊:Molecules (Basel, Switzerland)
    日期:2020-11-09
    DOI :10.3390/molecules25215199
    A novel series of pyrimidine-benzotriazole derivatives have been synthesized and evaluated for their anticancer activity against human solid tumor cell lines. The most promising molecule was identified for its excellent antiproliferative activities, especially against the SiHa cell line with IC value as 0.009 μM. Kinase inhibition assay assessed was a potential multi-kinase inhibitor, which possessed potent inhibitory activities against cyclin-dependent kinases (CDKs) and fms-like tyrosine kinase (FLT) with IC values in the nanomolar range. Molecular docking studies illustrated that the introduction of triazole moiety in was critical for CDKs inhibition. In addition, inhibited cancer cell proliferation, colony-formation, and cell cycle progression and provoked apoptotic death in vitro. In an SiHa xenograft mouse model, a once-daily dose of compound at 20 mg/kg significantly suppressed the tumor growth without obvious toxicity. Taken together, provided valuable guide for further structural optimization for CDKs and FLT inhibitors.
  • 3区Q2影响因子: 3.9
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    4. Lipidomic profiling reveals lipid regulation by a novel LSD1 inhibitor treatment.
    作者:Li Yan , Qian Xinying , Lin Yiyun , Tao Lei , Zuo Zeping , Zhang Huaqin , Yang Shengyong , Cen Xiaobo , Zhao Yinglan
    期刊:Oncology reports
    日期:2021-09-09
    DOI :10.3892/or.2021.8184
    Lipid metabolic alterations are associated with cancer progression. Lysine‑specific demethylase 1 (LSD1) plays a crucial role in cancer and has become a promising target for cancer therapy. However, the effect of LSD1 on lipid metabolism remains unclear. In the present study, we used a LC‑MS/MS‑based lipidomics approach to investigate the impact of LSD1 on cancer cell lipid metabolism using ZY0511, a specific LSD1 inhibitor developed by our group as a specific probe. ZY0511 profoundly modified the human colorectal and cervical cancer cell lipid metabolism. A total of 256 differential metabolites were identified in HeLa cells, and 218 differential metabolites were identified in HCT116 cells, respectively. Among these lipid metabolites, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and sphingomyelin (SM) were downregulated by ZY0511. In contrast, ceramide (Cer) and a small portion of glycerophospholipids such as phosphatidylinositol and phosphatidylethanolamine were upregulated by ZY0511. These results revealed a disturbance in sphingolipids (SPs) and glycerophospholipids, which may be correlated with the progression of cancer. Furthermore, a marked increase in Cer and prominent decrease in SM were consistent with the upregulated expression of key enzymes in the Cer synthesis process including synthesis, hydrolysis of SM and the salvage pathway after ZY0511 exposure. In conclusion, our research reveals a link between LSD1 and lipid metabolism in cancer cells, offering more comprehensive evidence for the application of LSD1 inhibitors for cancer therapy. The underlying mechanisms of how the LSD1 inhibitor regulates lipid metabolism warrant further investigation.
  • 3区Q1影响因子: 4.3
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    5. Virtual screening in small molecule discovery for epigenetic targets.
    作者:Li Guo-Bo , Yang Ling-Ling , Yuan Yiming , Zou Jun , Cao Yu , Yang Sheng-Yong , Xiang Rong , Xiang Mingli
    期刊:Methods (San Diego, Calif.)
    日期:2014-11-21
    DOI :10.1016/j.ymeth.2014.11.010
    Epigenetic modifications are critical mechanisms that regulate many biological processes and establish normal cellular phenotypes. Aberrant epigenetic modifications are frequently linked to the development and maintenance of several diseases including cancer, inflammation and metabolic diseases and so on. The key proteins that mediate epigenetic modifications have been thus recognized as potential therapeutic targets for these diseases. Consequently, discovery of small molecule inhibitors for epigenetic targets has received considerable attention in recent years. Here, virtual screening methods and their applications in the discovery of epigenetic target inhibitors are the focus of this review. Newly emerging approaches or strategies including rescoring methods, docking pose filtering methods, machine learning methods and 3D molecular similarity methods were also underlined. They are expected to be employed for identifying novel inhibitors targeting epigenetic regulation more efficiently.
  • 3区Q2影响因子: 4.6
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    6. 5-Methoxyquinoline Derivatives as a New Class of EZH2 Inhibitors.
    作者:Xiang Pu , Jie Hui , Zhou Yang , Yang Bo , Wang Hui-Juan , Hu Jing , Hu Jian , Yang Sheng-Yong , Zhao Ying-Lan
    期刊:Molecules (Basel, Switzerland)
    日期:2015-04-27
    DOI :10.3390/molecules20057620
    A series of quinoline derivatives was synthesized and biologically evaluated as Enhancer of Zeste Homologue 2 (EZH2) inhibitors. Structure-activity relationship (SAR) studies led to the discovery of 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (5k), which displayed an IC50 value of 1.2 μM against EZH2, decreased global H3K27me3 level in cells and also showed good anti-viability activities against two tumor cell lines. Due to the low molecular weight and the fact that no quinoline derivative has been reported as an EZH2 inhibitor, this compound could serve as a lead compound for further optimization.
  • 1区Q1影响因子: 10.1
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    7. ICAM3 mediates inflammatory signaling to promote cancer cell stemness.
    作者:Shen Wenzhi , Xie Junling , Zhao Shuangtao , Du Renle , Luo Xiaohe , He Huiwen , Jiang Shan , Hao Na , Chen Chong , Guo Chunlei , Liu Yanhua , Chen Yanan , Sun Peiqing , Yang Shengyong , Luo Na , Xiang Rong , Luo Yunping
    期刊:Cancer letters
    日期:2018-03-02
    DOI :10.1016/j.canlet.2018.02.034
    In this study, we present a medium throughput siRNA screen platform to identify inflammation genes that regulate cancer cell stemness. We identified several novel candidates that decrease OCT4 expression and reduce the ALDH + subpopulation both of which are characteristic of stemness. Furthermore, one of the novel candidates ICAM3 up-regulates in the ALDH + subpopulation, the side population and the developed spheres. ICAM3 knockdown reduces the side population, sphere formation and chemo-resistance in MDA-MB-231 human breast cancer cells and A549 lung cancer cells. In addition, mice bearing MDA-MB-231-shICAM3 cells develop smaller tumors and fewer lung metastases versus control. Interestingly, ICAM3 recruits and binds to Src by the YLPL motif in its intracellular domain which further activates the PI3K-AKT phosphorylation cascades. The activated p-AKT enhances SOX2 and OCT4 activity and thereby maintains cancer cell stemness. Meanwhile, the p-AKT facilitated p50 nuclear translocation/activation enhances p50 feedback and thereby promotes ICAM3 expression by binding to the ICAM3 promoter region. On this basis, Src and PI3K inhibitors suppress ICAM3-mediated signaling pathways and reduce chemo-resistance which results in tumor growth suppression in vitro and in vivo. In summary, we identify a potential CSC regulator and suggest a novel mechanism by which ICAM3 governs cancer cell stemness and inflammation.
  • 1区Q1影响因子: 6.8
    8. Discovery of 3,4-Dihydrobenzo[][1,4]oxazepin-5(2)-one Derivatives as a New Class of Selective TNIK Inhibitors and Evaluation of Their Anti-Colorectal Cancer Effects.
    期刊:Journal of medicinal chemistry
    日期:2022-01-05
    DOI :10.1021/acs.jmedchem.1c00672
    The Traf2- and Nck-interacting protein kinase (TNIK) is a downstream signal protein of the Wnt/β-catenin pathway and has been thought of as a potential target for the treatment of colorectal cancer (CRC) that is often associated with dysregulation of Wnt/β-catenin signaling pathway. Herein, we report the discovery of a series of 3,4-dihydrobenzo[][1,4]oxazepin-5(2)-one derivatives as a new class of TNIK inhibitors. Structure-activity relationship (SAR) analyses led to the identification of a number of potent TNIK inhibitors with compound being the most active one (IC: 0.026 ± 0.008 μM). This compound also displayed excellent selectivity for TNIK against 406 other kinases. Compound could efficiently suppress CRC cell proliferation and migration in assays and exhibited considerable antitumor activity in the HCT116 xenograft mouse model. It also showed favorable pharmacokinetic properties. Overall, could be a promising lead compound for drug discovery targeting TNIK and deserves further studies.
  • 4区Q2影响因子: 2.2
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    9. Discovery of small molecule FLT3 inhibitors that are able to overcome drug-resistant mutations.
    作者:Zhang Guo , Zhang Wenqing , Shen Chenjian , Nan Jinshan , Chen Ming , Lai Shusheng , Zhong Jiemin , Li Bolin , Wang Tianqi , Wang Yifei , Yang Shengyong , Li Linli
    期刊:Bioorganic & medicinal chemistry letters
    日期:2020-09-03
    DOI :10.1016/j.bmcl.2020.127532
    Herein we report the discovery of 1-(5-(tert-butyl)isoxazol-3-yl)-3- (3-fluorophenyl)urea derivatives as new FLT3 inhibitors that are able to overcome the drug resistance mutations: the secondary D835Y and F691L mutations on the basis of the internal tandem duplications (ITD) mutation of FLT3 (FLT3-ITD/D835Y and FLT3-ITD/F691L, respectively). The most potent compound corresponds to 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3- fluorophenyl)urea (4d), which showed ICs (half maximal inhibitory concentrations) of 0.072 nM, 5.86 nM and 3.48 nM against FLT3-ITD, FLT3-ITD/F691L and FLT3-ITD/D835Y, respectively. Compound 4d also showed good selectivity for FLT3 in a kinase profiling assay. Collectively, 4d could be a good lead compound and deserves further in-depth studies.
  • 1区Q1影响因子: 6.8
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    10. Discovery of Potent Small-Molecule SIRT6 Activators: Structure-Activity Relationship and Anti-Pancreatic Ductal Adenocarcinoma Activity.
    作者:Chen Xiuli , Sun Weining , Huang Shenzhen , Zhang Hailin , Lin Guifeng , Li Hui , Qiao Jingxin , Li Linli , Yang Shengyong
    期刊:Journal of medicinal chemistry
    日期:2020-09-09
    DOI :10.1021/acs.jmedchem.0c01183
    SIRT6 activation is thought to be a promising target for the treatment of many diseases, particularly cancer. Herein, we report the discovery of a series of new small-molecule SIRT6 activators. Structure-activity relationship analyses led to the identification of the most potent compound, 2-(1-benzofuran-2-yl)--(diphenylmethyl) quinoline-4-carboxamide (), which showed an EC value of 0.58 ± 0.12 μM and an EC value of 5.35 ± 0.69 μM against SIRT6-dependent peptide deacetylation in FLUOR DE LYS assay. It exhibited weak or no activity against other HDAC family members as well as 415 kinases, indicating good selectivity for SIRT6. significantly inhibited the proliferation and migration of pancreatic ductal adenocarcinoma (PDAC) cells . It also markedly suppressed the tumor growth in a PDAC tumor xenograft model. This compound showed attractive pharmacokinetic properties. Overall, could be a good lead compound for the treatment of PDAC, and it is worthy of further study.
  • 2区Q1影响因子: 5.9
    11. Identification of triazolopyridine derivatives as a new class of AhR agonists and evaluation of anti-psoriasis effect in a mouse model.
    作者:Tian Chenyu , Zhang Guo , Xia Ziyi , Chen Nanjun , Yang Shengyong , Li Linli
    期刊:European journal of medicinal chemistry
    日期:2022-01-20
    DOI :10.1016/j.ejmech.2022.114122
    The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, can regulate the immune balance of Th17/22 and Treg cells, which plays an important role in the development and maintenance of the skin barrier. We herein report the discovery of triazolopyridine derivatives as a new class of AhR agonists. Structure-activity relationship analyses led to the identification of the most active compound, 6-bromo-2-(4-bromophenyl)-[1,2,4]triazolo[1,5-a]pyridine (12a), with an EC (50% effective concentration) value of 0.03 nM. Compound 12a could induce rapid nuclear enrichment of AhR, trigger the transcription of downstream genes and promote skin barrier repair. Topical or oral administration of 12a could significantly alleviate imiquimod (IMQ)-induced psoriasis-like skin lesion. Considering the excellent in vivo anti-psoriasis activity as well as good pharmacokinetic properties, 12a could be a promising lead compound for drug discovery against psoriasis, and deserving further investigation.
  • 4区Q2影响因子: 2.2
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    12. Discovery of 6-phenylimidazo[2,1-b]thiazole derivatives as a new type of FLT3 inhibitors.
    作者:Lin Xing-Dong , Yang Hui-Wen , Ma Shuang , Li Wei-Wei , Zhang Chun-Hui , Wang Wen-Jing , Xiang Rong , Li Lin-Li , Yang Sheng-Yong
    期刊:Bioorganic & medicinal chemistry letters
    日期:2015-08-28
    DOI :10.1016/j.bmcl.2015.08.068
    In this investigation, a series of 6-phenylimidazo[2,1-b]thiazole derivatives were synthesized. Structure-activity relationship (SAR) analysis of these compounds based on cellular assays led to the discovery of a number of compounds that showed potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell line MV4-11, but very weak or no activity against FLT3-independent human cervical cancer cell line Hela. FLT3 kinase inhibition assays were then performed on the three most active compounds. Among these compounds, 6-(4-(3-(5-(tert-butyl)isoxazol- 3-yl)ureido)phenyl)-N-(3-(dimethylamino)propyl)imidazo[2,1-b]thiazole-3-carboxamide (19) exhibited the highest potency in both cellular (MV4-11, IC50: 0.002 μM) and enzymatic (FLT3, IC50: 0.022 μM) assays. Further in-depth in vitro anti-AML activity and mechanism of action studies were carried out on compound 19.
  • 4区Q2影响因子: 2.2
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    13. Discovery of 5-(4-methylpiperazin-1-yl)-2-nitroaniline derivatives as a new class of SIRT6 inhibitors.
    作者:Sun Weining , Chen Xiuli , Huang Shenzhen , Li Wenpei , Tian Chenyu , Yang Shengyong , Li Linli
    期刊:Bioorganic & medicinal chemistry letters
    日期:2020-04-25
    DOI :10.1016/j.bmcl.2020.127215
    SIRT6 is a deacetylase of histone H3 and inhibitors of SIRT6 have been thought as potential agents for treatment of diabetes. Herein we report the discovery of a series of new SIRT6 inhibitors containing the skeleton 1-phenylpiperazine. Among them, compound 5-(4-methylpiperazin-1-yl)-2-nitroaniline (6d) is the most potent one, which showed an IC value of 4.93 μM against SIRT6 in the Fluor de Lys (FDL) assay. It displayed K values of 9.76 μM and 10 μM in surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) assays, respectively. In selectivity assay, 6d showed no activity against other members of the HDAC family (SIRT1-3 and HDAC1-11) at concentrations up to 200 µM. In a mouse model of type 2 diabetes, 6d could significantly increase the level of glucose transporter GLUT-1, thereby reducing blood glucose. Overall, this study provides a promising lead compound for subsequent drug discovery targeting SIRT6.
  • 2区Q1影响因子: 5.9
    14. Discovery of a novel and potent inhibitor with differential species-specific effects against NLRP3 and AIM2 inflammasome-dependent pyroptosis.
    作者:Jiao Yan , Nan Jinshan , Mu Bo , Zhang Yun , Zhou Nenghua , Yang Shunhua , Zhang Shanshan , Lin Wanting , Wang Falu , Xia Anjie , Cao Zhixing , Chen Pei , Pan Zhiling , Lin Guifeng , Pan Shulei , Bin Huachao , Li Linli , Yang Shengyong
    期刊:European journal of medicinal chemistry
    日期:2022-02-11
    DOI :10.1016/j.ejmech.2022.114194
    The NLRP3 inflammasome, which regulated a proinflammatory programmed cell death form termed pyroptosis, is involved in the pathological process of various human diseases, such as multiple sclerosis, type 2 diabetes, and gout. Thus, compounds inhibiting activation of the NLRP3 inflammasome can be promising treatments for these diseases. In this study, we conducted a phenotypic screening against NLRP3-dependent pyroptosis and discovered the hit compound 1, which showed moderate antipyroptotic activity. Chemistry efforts to improve potency of 1 resulted in a novel compound 59 (J114), which exhibited a half-maximal inhibitory concentration (IC) of 0.077 ± 0.008 μM against cell pyroptosis. Interestingly, unlike all pyroptosis inhibitors currently reported, the activity of J114 showed significant differences in human- and mouse-derived cells. The IC of J114-mediated inhibition of IL-1β secretion by human THP-1 macrophages was 0.098 μM, which was nearly 150-fold and 500-fold more potent than that of J774A.1 (14.62 μM) and bone marrow-derived macrophages (BMDMs) (48.98 μM), respectively. Further studies showed that J114 displayed remarkable inhibitory activity against NLRP3- and AIM2-but not NLRC4-dependent activation of caspase-1 and the release of IL-1β in human THP-1 macrophages. Mechanistically, J114 disturbed the interaction of NLRP3 or AIM2 with the adaptor protein ASC and inhibited ASC oligomerization. Overall, our study identified a unique molecule that inhibits NLRP3 and AIM2 inflammasome activation and has species differences, which is worthy of further research to understand the differential regulation of the NLRP3 and AIM2 inflammasomes in humans and mice.
  • 2区Q1影响因子: 5.9
    15. Discovery of a potent, selective and cell active inhibitor of mA demethylase ALKBH5.
    期刊:European journal of medicinal chemistry
    日期:2022-05-11
    DOI :10.1016/j.ejmech.2022.114446
    AlkB homolog 5 (ALKBH5) is an RNA mA demethylase involved in the regulation of genes transcription, translation and metabolism and has been considered as a promising therapeutic target for various human diseases, especially cancers. However, there is still a lack of potent and selective ALKBH5 inhibitors. Herein, we report a new class of ALKBH5 inhibitors containing the 1-aryl-1H-pyrazole scaffold, which were obtained through fluorescence polarization-based screening, structural optimization and structure-activity relationship analysis. Among these compounds, 20m was the most potent one, which showed an IC value of 0.021 μM in fluorescence polarization assay. Compound 20m exhibited high selectivity towards ALKBH5 versus FTO as well as other AlkB subfamily members, indicating good selectivity for ALKBH5. Cellular thermal shift assay (CETSA) analysis showed that 20m could efficiently stabilize ALKBH5 in HepG2 cells. Dot blot assay demonstrated that 20m could increase mA level in intact cells. Collectively, 20m is a potent, selective and cell active ALKBH5 inhibitor and could be used as a versatile chemical probe to explore the biological function of ALKBH5.
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