作者: Belle, Roman ; Saraç, Hilal ; Corner, Thomas P ; Šimelis, Klemensas ; Schofield, Christopher J ; Salah, Eidarus ; Kawamura, Akane ; McAllister, Tom E ; Suga, Hiroaki ; Nishio, Kosuke ; Tumber, Anthony

Ten-Eleven Translocation (TET) enzymes are Fe(II)/2OG-dependent oxygenases that play important roles in epigenetic regulation, but selective inhibition of the TETs is an unmet challenge. We describe the profiling of previously identified TET1-binding macrocyclic peptides. TiP1 is established as a potent TET1 inhibitor (IC₅₀ = 0.26 µM) with excellent selectivity over other TETs and 2OG oxygenases. TiP1 alanine scanning reveals the critical roles of Trp10 and Glu11 residues for inhibition of TET isoenzymes. The results highlight the utility of the RaPID method to identify potent enzyme inhibitors with selectivity over closely related paralogues. The structure-activity relationship data generated herein may find utility in the development of chemical probes for the TETs.

2023-08-01·Bioelectrochemistry

A highly sensitive signal-on biosensor based on restriction enzyme-mediated molecular switch for detection of TET1

Article

作者: Wang, Fang ; Chen, Zilin ; Chen, Chen ; Cheng, Ying

Ten-eleven translocation 1 (TET1) is a member of the TET enzyme family of dioxygenases, which plays an important role in active DNA demethylation. Therefore, the sensitive TET1 detection could help us better understand DNA methylation-demethylation in epigenetics. Here we report a detection method that consists of electrode fabrication, TET1 modification, DNA digestion, signal-on oxidoreduction, and current peak monitoring. An exquisitely designed 5'end-G-rich oligodeoxynucleotide was synthesized bearing a methylated cytosine (5-mC), which formed into hairpin dsDNA with the MspI recognition sequence (C^mCGG/GGCC). Then hairpin dsDNA was fabricated onto gold nanoparticles modified glassy carbon electrode (DNA/AuNPs/GCE) via Au-S bond. The combination uses of restriction enzyme MspI and hemin converted fabricated-dsDNA into peroxidase-mimicking DNAzyme, thereby promoting the reduction of H₂O₂ with a current peak. However, the current peak was extremely decreased once TET1 and T4 β-GT were used in advance. We confirmed a delicately linear relationship matching between the current difference and TET1 activity from 0.7 to 10.5 ng μL^-1 with a detection limit of 0.027 ng μL^-1, which outcompeted the former methods at least one order of magnitudes. The TET1 activity evaluation in the existence of Bobcat339 was also tested as the proof of concept of inhibitors screening. Our strategy provides a novel, label-free, and sensitive electrochemical approach that enables us to complete both TET1 activity evaluation and potential TET1 inhibitors screening.

2023-03-29·Science Translational Medicine1区 · 医学

Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia

1区 · 医学

Article

作者: Wu, Xiwei ; Wu, Dong ; Chao, Jianfei ; Sheng, Yue ; He, Xin ; Nguyen, Le Xuan Truong ; Qian, Zhijian ; Ngo, Vu N ; Gu, Zhaohui ; Müschen, Markus ; Shi, Yanhong ; Leung, Keith ; Shen, Chao ; Han, Li ; Small, Andrew ; Qing, Ying ; Xue, Jianhuang ; Deng, Xiaolan ; Zhao, Zhicong ; Wang, Kitty ; Xu, Mingjiang ; Zhang, Bin ; Qin, Hanjun ; Prince, Emily ; Marcucci, Guido ; Weng, Hengyou ; Tan, Brandon ; Zhou, Keren ; Xiao, Gang ; Chen, Jianjun ; Cai, Zhenming ; Chen, Zhenhua ; Qin, Xi ; Li, Yangchan ; Zhang, Zheng ; Su, Rui ; Huang, Huilin ; Li, Wei ; Chen, Yu ; Dong, Lei

Although the overall survival rate of B cell acute lymphoblastic leukemia (B-ALL) in childhood is more than 80%, it is merely 30% in refractory/relapsed and adult patients with B-ALL. This demonstrates a need for improved therapy targeting this subgroup of B-ALL. Here, we show that the ten-eleven translocation 1 (TET1) protein, a dioxygenase involved in DNA demethylation, is overexpressed and plays a crucial oncogenic role independent of its catalytic activity in B-ALL. Consistent with its oncogenic role in B-ALL, overexpression of TET1 alone in normal precursor B cells is sufficient to transform the cells and cause B-ALL in mice within 3 to 4 months. We found that TET1 protein is stabilized and overexpressed because of its phosphorylation mediated by protein kinase C epsilon (PRKCE) and ATM serine/threonine kinase (ATM), which are also overexpressed in B-ALL. Mechanistically, TET1 recruits STAT5B to the promoters of CD72 and JCHAIN and promotes their transcription, which in turn promotes B-ALL development. Destabilization of TET1 protein by treatment with PKC or ATM inhibitors (staurosporine or AZD0156; both tested in clinical trials), or by pharmacological targeting of STAT5B, greatly decreases B-ALL cell viability and inhibits B-ALL progression in vitro and in vivo. The combination of AZD0156 with staurosporine or vincristine exhibits a synergistic effect on inhibition of refractory/relapsed B-ALL cell survival and leukemia progression in PDX models. Collectively, our study reveals an oncogenic role of the phosphorylated TET1 protein in B-ALL independent of its catalytic activity and highlights the therapeutic potential of targeting TET1 signaling for the treatment of refractory/relapsed B-ALL.

100 项与 TET1 inhibitor(Beckman Research Institute) 相关的药物交易

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