Screen-identified selective inhibitor of lysine demethylase 5A blocks cancer cell growth and drug resistance.
Screen-identified selective inhibitor of lysine demethylase 5A blocks cancer cell growth and drug resistance.
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DOI：
10.18632/oncotarget.9539
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Yan Q
中科院分区：
文献类型：
--
作者：
Gale M;Sayegh J;Cao J;Norcia M;Gareiss P;Hoyer D;Merkel JS;Yan Q
赖氨酸脱甲基酶5A（KDM 5A/RBP 2/JARID 1A）是一种组蛋白赖氨酸脱甲基酶，其在包括肺癌、胃癌、乳腺癌和肝癌在内的多种人类癌症中过表达。它在重要的癌症过程中发挥关键作用，包括肿瘤发生、转移和药物耐受，使其成为潜在的癌症治疗靶点。分析KDM 5A脱甲基酶活性的化学工具非常有限，因为可用的抑制剂对KDM 5A没有特异性。在这里，我们使用基于均匀发光的测定来表征KDM 5A，并对约9，000个小分子进行了抑制剂筛选。从该筛选中，我们鉴定了几种3-硫代-1，2，4-三唑化合物，其抑制KDM 5A的体外IC 50值较低μM。重要的是，这些化合物显示出很大的特异性，并且不抑制其密切同源物KDM 5 B（PLU 1/JARID 1B）或相关的H3 K27脱甲基酶KDM 6A（UTX）和KDM 6 B（JMJD 3）。一种名为YUKA 1的化合物能够增加人类细胞中的H3 K4 me 3水平，并选择性地抑制依赖KDM 5A生长的癌细胞的增殖。由于KDM 5A被证明介导药物耐受性，我们研究了YUKA 1在用吉非替尼处理的EGFR突变型肺癌细胞和用曲妥珠单抗处理的HER 2+乳腺癌细胞中预防药物耐受性的能力。值得注意的是，这种化合物阻碍了耐药细胞的出现，突出了KDM 5A脱甲基酶活性在耐药性中的关键作用。这里提出的小分子是进一步研究KDM 5A脱甲基酶活性及其对癌症的贡献的极好工具化合物。
Lysine demethylase 5A (KDM5A/RBP2/JARID1A) is a histone lysine demethylase that is overexpressed in several human cancers including lung, gastric, breast and liver cancers. It plays key roles in important cancer processes including tumorigenesis, metastasis, and drug tolerance, making it a potential cancer therapeutic target. Chemical tools to analyze KDM5A demethylase activity are extremely limited as available inhibitors are not specific for KDM5A. Here, we characterized KDM5A using a homogeneous luminescence-based assay and conducted a screen of about 9,000 small molecules for inhibitors. From this screen, we identified several 3-thio-1,2,4-triazole compounds that inhibited KDM5A with low μM in vitro IC50 values. Importantly, these compounds showed great specificity and did not inhibit its close homologue KDM5B (PLU1/JARID1B) or the related H3K27 demethylases KDM6A (UTX) and KDM6B (JMJD3). One compound, named YUKA1, was able to increase H3K4me3 levels in human cells and selectively inhibit the proliferation of cancer cells whose growth depends on KDM5A. As KDM5A was shown to mediate drug tolerance, we investigated the ability of YUKA1 to prevent drug tolerance in EGFR-mutant lung cancer cells treated with gefitinib and HER2+ breast cancer cells treated with trastuzumab. Remarkably, this compound hindered the emergence of drug-tolerant cells, highlighting the critical role of KDM5A demethylase activity in drug resistance. The small molecules presented here are excellent tool compounds for further study of KDM5A's demethylase activity and its contributions to cancer.
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