Discovery of two novel ALKBH5 selective inhibitors that exhibit uncompetitive or competitive type and suppress the growth activity of glioblastoma multiforme
Discovery of two novel ALKBH5 selective inhibitors that exhibit uncompetitive or competitive type and suppress the growth activity of glioblastoma multiforme
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DOI：
10.1111/cbdd.14051
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发表时间：
2022-04
影响因子：
3
通讯作者：
Hikaru Takahashi;H. Hase;T. Yoshida;Junki Tashiro;Yoshihiro Hirade;K. Kitae;K. Tsujikawa
中科院分区：
文献类型：
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作者：
Hikaru Takahashi;H. Hase;T. Yoshida;Junki Tashiro;Yoshihiro Hirade;K. Kitae;K. Tsujikawa
一组RNA甲基化酶是目前感兴趣的癌症治疗的新靶点。α-酮戊二酸依赖性双加氧酶B（Alk B）同系物5（ALKBH 5）是一种N6-甲基腺苷（m6 A）脱甲基酶，通过高通量筛选纯小分子化合物，我们鉴定出两种新的抑制剂Ena 15和Ena 21，每种化合物对2-酮戊二酸（2 OG）均表现出非竞争性或竞争性抑制。此外，Ena 21对脂肪量和肥胖相关蛋白（FTO）几乎没有抑制活性，FTO是另一种N6-甲基腺苷脱甲基酶，而Ena 15增强了FTO的脱甲基酶活性。具有ALKBH 5（PDB ID：4 NRO）晶体结构的两种化合物的预测结合位姿与关于该酶动力学中2 OG催化位点的相互作用的这些观察结果相当。此外，ALKBH 5的敲低或Ena 15或Ena 21的抑制了多形性胶质母细胞瘤衍生细胞系的细胞增殖，减少了细胞周期合成期的细胞群，增加了m6 A RNA水平，并稳定了FOXM 1 mRNA。基于这些结果，发现Ena 15和Ena 21是潜在的候选者，可能有助于进一步研究ALKBH 5的生物学功能。
A group of RNA methylation enzymes is currently of interest as a new target for cancer therapy. Alpha‐ketoglutarate‐dependent dioxygenase B (AlkB) homolog 5 (ALKBH5) is an N6‑methyladenosine (m6A) demethylation enzyme, and by high‐throughput screening from pure small molecule compounds, we identified two novel inhibitors, Ena15 and Ena21, against it. Each compound showed either uncompetitive or competitive inhibition for 2‐oxoglutarate (2OG). In addition, Ena21 had little inhibitory activity for fat mass and obesity‐associated protein (FTO), which is another N6‑methyladenosine demethylation enzyme, while Ena15 enhanced the demethylase activity of FTO. The predicted binding poses of both compounds with the crystal structure of ALKBH5 (PDB ID: 4NRO) were comparable with these observations pertaining to the interaction of the 2OG catalytic site in this enzyme kinetics. Furthermore, either knockdown of ALKBH5 or inhibition with Ena15 or Ena21 inhibited cell proliferation of glioblastoma multiforme‐derived cell lines, decreased cell population in the synthesis phase of the cell cycle, increased m6A RNA level, and stabilized FOXM1 mRNA. Based on these results, Ena15 and Ena21 were found to be potential candidates that might help in further research into the biological function of ALKBH5.