Design of thienopyranone-based BET inhibitors that bind multiple synthetic lethality targets
Design of thienopyranone-based BET inhibitors that bind multiple synthetic lethality targets
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DOI：
10.1038/s41598-020-68964-6
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发表时间：
2020-07-21
影响因子：
4.6
通讯作者：
Kutateladze, Tatiana G.
中科院分区：
文献类型：
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作者：
Vann, Kendra R.;Pal, Dhananjaya;Kutateladze, Tatiana G.
针对几种癌症驱动因素的小分子化合物的开发显示出巨大的治疗潜力。在这里，我们开发了新一代高效的基于噻吩吡喃酮（TP）的转录调节因子BRD4的BET溴域（bd）抑制剂，这些抑制剂能够同时结合磷脂酰肌醇-3激酶（PI3K）和/或细胞周期蛋白依赖性激酶4/6 （CDK4/6）。通过对配合物的晶体结构分析、核磁共振滴定实验和IC50测量，揭示了这些化合物对BRD4的抑制作用和选择性的分子基础。这些抑制剂在多种癌细胞系中显示出强大的细胞毒作用，并诱导细胞周期阻滞和细胞凋亡。我们进一步证明，TP抑制剂同时破坏BRD4的乙酰赖氨酸结合功能以及PI3K和CDK4/6的激酶活性，可提高几种癌症模型的疗效。总之，这些发现提供了进一步令人信服的证据，证明这些多作用抑制剂比单一抑制化学型更有效。
Development of small molecule compounds that target several cancer drivers has shown great therapeutic potential. Here, we developed a new generation of highly potent thienopyranone (TP)-based inhibitors for the BET bromodomains (BDs) of the transcriptional regulator BRD4 that have the ability to simultaneously bind to phosphatidylinositol-3 kinase (PI3K) and/or cyclin-dependent kinases 4/6 (CDK4/6). Analysis of the crystal structures of the complexes, NMR titration experiments and IC50 measurements reveal the molecular basis underlying the inhibitory effects and selectivity of these compounds toward BDs of BRD4. The inhibitors show robust cytotoxic effects in multiple cancer cell lines and induce cell-cycle arrest and apoptosis. We further demonstrate that concurrent disruption of the acetyllysine binding function of BRD4 and the kinase activities of PI3K and CDK4/6 by the TP inhibitor improves efficacy in several cancer models. Together, these findings provide further compelling evidence that these multi-action inhibitors are efficacious and more potent than single inhibitory chemotypes.