Binding pocket-based design, synthesis and biological evaluation of novel selective BRD4-BD1 inhibitors.,Bioorganic & Medicinal Chemistry

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Binding pocket-based design, synthesis and biological evaluation of novel selective BRD4-BD1 inhibitors.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-03-22 , DOI: 10.1016/j.bmc.2019.03.037
Junlong Ma ₁ , Heng Chen ₂ , Jie Yang ₂ , Zutao Yu ₂ , Pan Huang ₂ , Haofeng Yang ₂ , Bifeng Zheng ₂ , Rangru Liu ₃ , Qianbin Li ₂ , Gaoyun Hu ₂ , Zhuo Chen ₂

Affiliation

Bromodomain-containing protein 4 (BRD4), consisting of two tandem bromodomains (BD1 and BD2), is key epigenetic regulator in fibrosis and cancer, which has been reported that BD1 and BD2 have distinct roles in post-translational modification. But there are few selective inhibitors toward those two domains. Herein, this study designed and synthesized a series of novel selective BRD4-BD1 inhibitors, using computer-aided drug design (CADD) approach focused on exploring the difference of the binding pockets of BD1 and BD2, and finding the His437 a crucial way to achieve BRD4-BD1 selectivity. Our results revealed that the compound 3u is a potent selective BRD4-BD1 inhibitor with IC50 values of 0.56 μM for BD1 but >100 μM for BD2. The compound exhibited a broad spectrum of anti-proliferative activity against several human cancer and fibroblastic cell lines, which might be related to its capability of reducing the expression of c-Myc and collagen I. Furthermore, it could induce apoptosis in A375 cells. To the contrary, the selective BD2 inhibitor, RVX-208, did not indicate any of these activities. Our findings highlight that the function of BRD4-BD1 might be predominant in fibrosis and cancer. And it is rational to further develop novel selective BRD4-BD1 inhibitors.

中文翻译：

基于结合口袋的新型选择性BRD4-BD1抑制剂的设计，合成和生物学评估。

含溴结构域的蛋白质4（BRD4）由两个串联的溴结构域（BD1和BD2）组成，是纤维化和癌症中的关键表观遗传调控因子，据报道BD1和BD2在翻译后修饰中具有独特的作用。但是，针对这两个域的选择性抑制剂很少。本文中，本研究使用计算机辅助药物设计（CADD）方法设计并合成了一系列新型选择性BRD4-BD1抑制剂，重点在于探索BD1和BD2结合口袋的差异，并发现His437是实现这一目标的关键途径BRD4-BD1选择性。我们的结果表明，化合物3u是一种有效的选择性BRD4-BD1抑制剂，BD1的IC50值为0.56μM，而BD2的IC50值为> 100μM。该化合物对几种人类癌症和成纤维细胞系具有广泛的抗增殖活性，这可能与其降低c-Myc和胶原I的表达能力有关。此外，它还可以诱导A375细胞凋亡。相反，选择性BD2抑制剂RVX-208没有显示任何这些活性。我们的发现突出表明BRD4-BD1的功能可能在纤维化和癌症中占主导地位。进一步开发新型选择性BRD4-BD1抑制剂是合理的。我们的发现突出表明BRD4-BD1的功能可能在纤维化和癌症中占主导地位。进一步开发新型选择性BRD4-BD1抑制剂是合理的。我们的发现突出表明BRD4-BD1的功能可能在纤维化和癌症中占主导地位。进一步开发新型选择性BRD4-BD1抑制剂是合理的。

更新日期：2019-03-22

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