McKeown Michael R, Shaw Daniel L, Fu Harry, Liu Shuai, Xu Xiang, Marineau Jason J, Huang Yibo, Zhang Xiaofeng, Buckley Dennis L, Kadam Asha, Zhang Zijuan, Blacklow Stephen C, Qi Jun, Zhang Wei, Bradner James E
Department of Medical Oncology, Dana-Farber Cancer Institute , 450 Brookline Avenue, Boston, Massachusetts 02215, United States.
J Med Chem. 2014 Nov 13;57(21):9019-27. doi: 10.1021/jm501120z. Epub 2014 Oct 31.
BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 Å resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors.
BET溴结构域抑制作用为基因调控带来了新见解，并成为一种有前景的癌症治疗策略。早期甲基三唑并BET抑制剂的结构相似性促使人们需要结构不同的配体作为溴结构域功能的探针。利用含氟标记的多组分反应，我们围绕一个3,5-二甲基异恶唑偏向元件开发了一个聚焦化学文库，其中的溴结构域抑制剂具有微摩尔级别的生化IC50。通过迭代合成和生化评估，基于咪唑并[1,2-a]吡嗪支架优化了新型BET溴结构域抑制剂。先导化合物32（UMB-32）与BRD4结合，解离常数（Kd）为550 nM，在BRD4依赖的细胞系中细胞活性为724 nM。此外，化合物32对TAF1（一种此前未被发现化学方法涉及的含溴结构域转录因子）也有活性。化合物32与BRD4共结晶，得到分辨率为1.56 Å的晶体结构。这项研究展示了含氟和多组分化学合成在新型表观遗传抑制剂开发中的新应用。
