First-in-Class Inhibitors of the Ribosomal Oxygenase MINA53.
First-in-Class Inhibitors of the Ribosomal Oxygenase MINA53.
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DOI：
10.1021/acs.jmedchem.1c00605
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发表时间：
2021-12-09
影响因子：
7.3
通讯作者：
Rotili D
中科院分区：
文献类型：
--
作者：
Nowak RP;Tumber A;Hendrix E;Ansari MSZ;Sabatino M;Antonini L;Andrijes R;Salah E;Mautone N;Pellegrini FR;Simelis K;Kawamura A;Johansson C;Passeri D;Pellicciari R;Ciogli A;Del Bufalo D;Ragno R;Coleman ML;Trisciuoglio D;Mai A;Oppermann U;Schofield CJ;Rotili D
MINA53是一种JmjC结构域2-氧戊二酸依赖的加氧酶，催化核糖体羟化，是致癌转录因子c-myc的靶标。尽管它具有抗癌的靶向潜力，但还没有小分子MINA53抑制剂的报道。利用核糖体底物片段，我们建立了MINA53和相关的加氧酶NO66的质谱分析。这些测定使2-(aryl)alkylthio-3，4-dihydro-4-oxoypyrimidine-5-carboxylic酸能够被鉴定为有效的MINA53抑制剂，比NO66和其他JMJC加氧酶具有选择性。JmjC脱甲基酶KDM5B的结晶学研究表明，这些抑制剂通过与铁辅酶的直接作用结合到MINA53上，但没有直接的金属螯合作用。MINA53抑制剂显示了MINA53相对于KDM4-6的靶向结合和选择性。MINA53抑制剂显示出与实体癌细胞的抗增殖活性，并使癌细胞对常规化疗敏感，这表明进一步研究其在联合治疗中的潜力是必要的。
MINA53 is a JmjC domain 2-oxoglutarate-dependent oxygenase that catalyzes ribosomal hydroxylation and is a target of the oncogenic transcription factor c-MYC. Despite its anticancer target potential, no small-molecule MINA53 inhibitors are reported. Using ribosomal substrate fragments, we developed mass spectrometry assays for MINA53 and the related oxygenase NO66. These assays enabled the identification of 2-(aryl)alkylthio-3,4-dihydro-4-oxoypyrimidine-5-carboxylic acids as potent MINA53 inhibitors, with selectivity over NO66 and other JmjC oxygenases. Crystallographic studies with the JmjC demethylase KDM5B revealed active site binding but without direct metal chelation; however, molecular modeling investigations indicated that the inhibitors bind to MINA53 by directly interacting with the iron cofactor. The MINA53 inhibitors manifest evidence for target engagement and selectivity for MINA53 over KDM4–6. The MINA53 inhibitors show antiproliferative activity with solid cancer lines and sensitize cancer cells to conventional chemotherapy, suggesting that further work investigating their potential in combination therapies is warranted.
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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
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
--
作者：
Hutchinson, Sue E.;Leveridge, Melanie V.;Argyrou, Argyrides
通讯作者：
Argyrou, Argyrides
影响因子：
2.9
作者：
Kawamura A;Tumber A;Rose NR;King ON;Daniel M;Oppermann U;Heightman TD;Schofield C
通讯作者：
Schofield C