BCR ABL1 transcript: e13a2 versus e14a2, Most mRNAs transcribed from BCR ABL1

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BCR ABL1 transcript: e13a2 versus e14a2, Most mRNAs transcribed from BCR ABL1

Mensagem  wangqian em Seg Fev 10, 2014 1:49 am

recently questioned its selectivity against STAT3, It exhibited an IC50 of 5. 1 uM in a fluorescence polarization assay and demon strated increases in apoptotic rate of STAT3 dependent breast and hepatic cancer cells. Lin and colleagues performed structure based virtual screening of more than 425,000 compounds form four 17-AAG 分子量 different chemical libraries to search a suitable STAT3 inhibitor. Out of top 200 compounds, they tested 100 chemicals with in vitro cell luciferase assay and found STA 21, a deoxytetrangomycin, as the most promising compound, It binds with SH2 domain of STAT3 and effectively inhibits STAT3 dimerization and demonstrated inhibition of growth and survival of breast and soft tissue sarcoma cell lines, The same group developed a structural analogue of STA 21, LLL 3.<br><br> This molecule has better cellular perme ability than STA 21. Initially they treated human glioblastoma cell lines with LLL 3 in vitro and observed decreased viability of tumor cells, The effi cacy was also demonstrated by the observation that LLL 3 treated nude mice with intracranial glioblastoma lived longer than those treated with placebo, 17-DMAG ic50 Con stitutive activation of STAT3 and STAT5 is observed in chronic myelogenous leukemic cells due to activity of Abl kinase, therefore Mencalha and colleagues treated K562 leukemic cells with LLL 3. They demonstrated that it decreased tumor cell survival and possesses synergistic effect with Imatinib, For further optimization of LLL 3, Lin and colleagues replaced its acetyl group with sulfonamide and devel oped another STAT3 inhibitor, LLL12, It spe cifically prevents phosphorylation of Tyr 705 residue of STAT3 with IC50 ranging from 0.<br><br> 16 uM to 3. 09 uM in various human cancer cell lines including HPAC, U87, U373, PANC1, and SK BR 3, More recently, an other non peptide cell permeable, small molecule, called as A66 価格 XZH 5, was studied. In the docking model, it binds with SH2 domain of STAT3 and prevents STAT3 phos phorylation at Tyr705, leading to inhibition of down stream STAT3 activities and apoptosis in multiple cancer cell lines including breast, pancreatic, hepatocel lular carcinoma and rhabdomyosarcoma, Structure based high throughput virtual screening of the National Cancer Institute chemical libraries identified another potent STAT3 inhibitor, S31 201. Its salicylic acid moiety docks with pTyr binding site of STAT3 SH2 domain.<br><br> S31 201 inhibited proliferation of hepatocellular and breast can cer cells in mice, However GOLD docking studies suggested suboptimal interaction between STAT3 and S31 201. In an effort to improve this interaction, several molecules were rationally developed by Fletcher et al. Of these SF 1066 and SF 1087 are noteworthy with IC50 of 37 uM and 24 uM respectively in DU145 cell line, They also reported 16 novel sulphonea mide analogues of SF 1066. Among those, 17o effectively inhibited STAT3:STAT3 interaction and was considered to be the most potent. Authors demon strated that inhibition of STAT3 function in breast and myeloma cancer cells correlated with increased cell death, Matsuno et al. recognized STX 0119, a derivative of N 4 quinolinecarboxamide by virtual screen using a custom ized version of DOCK4 program with the crystal struc ture of STAT3.

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