Thyroid cancer (TC) is a very common malignancy worldwide. Chief among the innovative molecular drug targets for TC are epigenetic modifications. Increased telomerase activity in cancer cells makes telomerase a novel target for epigenetic anticancer drug innovation. Recently, telomerase reverse transcriptase (TERT) gene promoter (TERTp) mutations (C228T and C250T) were reported at high frequency in TC cell lines and tumor biopsies. In this study, three representative TC cell lines, mutant TERTp (TPC1), mutant BRAF/TERTp (KTC2), and wild-type TERTp (WRO), were screened with a drug library composed of 51 epigenetic drugs: 14 Aurora kinase inhibitors; 23 histone deacetylase inhibitors; 5 sirtuin modifiers; 3 hypoxia-inducible factor inhibitors; 2 DNA methyltransferase inhibitors; 2 histone methyltransferase inhibitors, a histone demethylase inhibitor, and a bromodomain inhibitor. Effects of the drugs on cell growth at 48 and 72 h were compared. PF-03814735, a small-molecule inhibitor of Aurora kinase A (IC50 = 0.8 nM) and B (IC50 = 5 nM), was the most potent on KTC2 cells, whereas CUDC-101, a multitarget inhibitor, was effective on both WRO and KTC2 cells. Notably, PF-03814735 was found to be the most effective epigenetic drug on cell lines harboring the C228T mutation. In conclusion, these new findings offer specific guidance on dose and time course selection to design novel therapeutic interventions against TC using PF-03814735, and specifically target cells carrying the TERTpC228T mutation. In a larger context of drug discovery science, these findings inform new strategies to forecast optimal treatment regimens for TC, particularly with Aurora kinase inhibitors and in ways guided by epigenetic drug design.

中文翻译：

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甲状腺癌的体外表观遗传药物设计：极光激酶抑制剂PF-03814735的承诺。

甲状腺癌（TC）是世界范围内非常常见的恶性肿瘤。TC创新分子药物靶标中的主要是表观遗传修饰。癌细胞中端粒酶活性的提高使端粒酶成为表观遗传抗癌药物创新的新靶标。最近，在TC细胞系和肿瘤活检中报道了端粒酶逆转录酶（TERT）基因启动子（TERTp）突变（C228T和C250T）。在这项研究中，使用由51种表观遗传药物组成的药物库筛选了三种代表性的TC细胞系，突变体TERTp（TPC1），突变体BRAF / TERTp（KTC2）和野生型TERTp（WRO）：14种Aurora激酶抑制剂；23种组蛋白脱乙酰基酶抑制剂；5个sirtuin修饰符；3种缺氧诱导因子抑制剂；2种DNA甲基转移酶抑制剂；2种组蛋白甲基转移酶抑制剂，一种组蛋白脱甲基酶抑制剂，和一个溴结构域抑制剂。比较了这些药物对48和72 h细胞生长的影响。PF-03814735是Aurora激酶A（IC50 = 0.8 nM）和B（IC50 = 5 nM）的小分子抑制剂，对KTC2细胞最有效，而多靶点抑制剂CUDC-101对WRO均有效和KTC2细胞。值得注意的是，PF-03814735被发现是具有C228T突变的细胞系上最有效的表观遗传药物。总之，这些新发现为剂量和时程选择提供了特定的指导，以设计使用PF-03814735的针对TC的新型治疗性干预措施，并特别针对携带TERTpC228T突变的靶细胞。在更广泛的药物发现科学背景下，这些发现为预测TC最佳治疗方案的新策略提供了依据，