Bromodomain (BRD) and extra-terminal (BET) proteins are epigenetic readers that regulate gene expression and promote cancer evolution. Pharmacological inactivation of BRD4 has recently been introduced as a promising anti-neoplastic approach that targets MYC oncogene expression. However, resistance against BRD4-targeting drugs has been described. We compared the efficacy of the small-molecule-type BET BRD inhibitor JQ1 with the recently developed BET protein degraders dBET1 and dBET6 in colon, breast, melanoma, ovarian, lung and prostate cancer cell lines. As determined by qPCR, all BRD4 targeting drugs dose-dependently decreased MYC expression, with dBET6 introducing the strongest downregulation of MYC. This correlated with the anti-proliferative activity of these drugs, which was at least one order of magnitude higher for dBET6 (IC50 0.001-0.5 µM) than for dBET1 or JQ1 (IC50 0.5-5 µM). Interestingly, when combined with commonly used cytotoxic therapeutics, dBET6 was found to promote anti-neoplastic effects and to counteract chemoresistance in most cancer cell lines. Moreover, JQ1 and both BET degraders strongly downregulated baseline and interferon-gamma induced expression of the immune checkpoint molecule PD-L1 in all cancer cell lines. Together, our data suggest that dBET6 outperforms first-generation BRD4 targeting drugs like dBET1 and JQ1, and decreases chemoresistance and immune resistance of cancer.

中文翻译：

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BRD4 的降解——一种有前途的治疗方法，不仅适用于血液肿瘤，而且适用于实体癌。

溴结构域 (BRD) 和末端外 (BET) 蛋白是调节基因表达和促进癌症进化的表观遗传阅读器。最近引入了 BRD4 的药理学灭活作为靶向 MYC 癌基因表达的有前途的抗肿瘤方法。然而，已经描述了对 BRD4 靶向药物的耐药性。我们比较了小分子型 BET BRD 抑制剂 JQ1 与最近开发的 BET 蛋白降解剂 dBET1 和 dBET6 在结肠癌、乳腺癌、黑色素瘤、卵巢癌、肺癌和前列腺癌细胞系中的功效。正如 qPCR 所确定的，所有 BRD4 靶向药物剂量依赖性地降低 MYC 表达，其中 dBET6 引入了最强的 MYC 下调。这与这些药物的抗增殖活性相关，dBET6 的抗增殖活性至少高出一个数量级（IC50 0.001-0. 5 µM) 比 dBET1 或 JQ1 (IC50 0.5-5 µM)。有趣的是，当与常用的细胞毒疗法结合时，发现 dBET6 可促进抗肿瘤作用并抵消大多数癌细胞系的化学抗性。此外，JQ1 和两种 BET 降解剂强烈下调基线和干扰素-γ 诱导的免疫检查点分子 PD-L1 在所有癌细胞系中的表达。总之，我们的数据表明，dBET6 优于第一代 BRD4 靶向药物，如 dBET1 和 JQ1，并降低癌症的化学抗性和免疫抗性。JQ1 和两种 BET 降解剂强烈下调基线和干扰素-γ 诱导的免疫检查点分子 PD-L1 在所有癌细胞系中的表达。总之，我们的数据表明，dBET6 优于第一代 BRD4 靶向药物，如 dBET1 和 JQ1，并降低癌症的化学抗性和免疫抗性。JQ1 和两种 BET 降解剂强烈下调基线和干扰素-γ 诱导的免疫检查点分子 PD-L1 在所有癌细胞系中的表达。总之，我们的数据表明，dBET6 优于第一代 BRD4 靶向药物，如 dBET1 和 JQ1，并降低癌症的化学抗性和免疫抗性。