Discovery of a Highly Selective Cell-Active Inhibitor of the Histone Lysine Demethylases KDM2/7.
Discovery of a Highly Selective Cell-Active Inhibitor of the Histone Lysine Demethylases KDM2/7.
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DOI：
10.1002/anie.201706788
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发表时间：
2017-12-04
期刊：
影响因子：
--
通讯作者：
Smith MD
中科院分区：
文献类型：
--
作者：
Gerken PA;Wolstenhulme JR;Tumber A;Hatch SB;Zhang Y;Müller S;Chandler SA;Mair B;Li F;Nijman SMB;Konietzny R;Szommer T;Yapp C;Fedorov O;Benesch JLP;Vedadi M;Kessler BM;Kawamura A;Brennan PE;Smith MD
组蛋白赖氨酸脱甲基酶（KDM）在基因表达的表观遗传调控中至关重要，但这些酶的选择性，细胞渗透性抑制剂或合适的工具化合物很少。我们描述了一类新的抑制剂的发现，这是非常有效的组蛋白赖氨酸脱甲基酶KDM 2A/7A。使用模块化合成方法探索化学空间并加速关键结构-活性关系的研究，从而开发出对KDM 2A/7A的选择性约为其他KDM的75倍的小分子，以及在低微摩尔浓度下的细胞活性。
Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell‐permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure–activity relationships, leading to the development of a small molecule with around 75‐fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.
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蛋白质甲基转移酶和去甲基酶抑制剂。
影响因子：
62.1
作者：
Kaniskan HÜ;Martini ML;Jin J
通讯作者：
Jin J
影响因子：
8.4
作者：
Hopkinson RJ;Tumber A;Yapp C;Chowdhury R;Aik W;Che KH;Li XS;Kristensen JBL;King ONF;Chan MC;Yeoh KK;Choi H;Walport LJ;Thinnes CC;Bush JT;Lejeune C;Rydzik AM;Rose NR;Bagg EA;McDonough MA;Krojer T;Yue WW;Ng SS;Olsen L;Brennan PE;Oppermann U;Muller-Knapp S;Klose RJ;Ratcliffe PJ;Schofield CJ;Kawamura A
通讯作者：
Kawamura A
影响因子：
--
作者：
England KS;Tumber A;Krojer T;Scozzafava G;Ng SS;Daniel M;Szykowska A;Che K;von Delft F;Burgess-Brown NA;Kawamura A;Schofield CJ;Brennan PE
通讯作者：
Brennan PE
影响因子：
16.6
作者：
Kawamura A;Münzel M;Kojima T;Yapp C;Bhushan B;Goto Y;Tumber A;Katoh T;King ON;Passioura T;Walport LJ;Hatch SB;Madden S;Müller S;Brennan PE;Chowdhury R;Hopkinson RJ;Suga H;Schofield CJ
通讯作者：
Schofield CJ
影响因子：
3.9
作者：
Hatch SB;Yapp C;Montenegro RC;Savitsky P;Gamble V;Tumber A;Ruda GF;Bavetsias V;Fedorov O;Atrash B;Raynaud F;Lanigan R;Carmichael L;Tomlin K;Burke R;Westaway SM;Brown JA;Prinjha RK;Martinez ED;Oppermann U;Schofield CJ;Bountra C;Kawamura A;Blagg J;Brennan PE;Rossanese O;Müller S
通讯作者：
Müller S