Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics.
Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics.
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DOI：
10.1158/1535-7163.mct-16-0568-t
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发表时间：
2017-06
影响因子：
5.7
通讯作者：
Schönbrunn E
中科院分区：
文献类型：
--
作者：
Ember SW;Lambert QT;Berndt N;Gunawan S;Ayaz M;Tauro M;Zhu JY;Cranfill PJ;Greninger P;Lynch CC;Benes CH;Lawrence HR;Reuther GW;Lawrence NJ;Schönbrunn E
已经报道了激酶和BET布罗莫结构域抑制剂在细胞杀伤中对多种癌症的协同作用。使用JAK 2抑制剂TG 101348的化学支架，我们开发并表征了单一药物，这些药物可以有效且同时抑制BRD 4和一组特定的致癌酪氨酸激酶，包括JAK 2、FLT 3、RET和ROS 1。先导化合物在几种血液癌细胞系中显示出靶向抑制作用，并且在抑制骨髓增生性肿瘤（MPN）患者的造血祖细胞生长方面非常有效。在931个癌细胞系中的筛选揭示了差异生长抑制潜力，其对骨癌和血癌具有最高活性，并且比单一BET抑制剂JQ 1的活性大大增强。基因-药物敏感性分析和药物组合研究表明BRD 4和激酶抑制的协同作用是细胞杀伤中上级效力的合理原因。结合起来，我们的研究结果表明，这些药物作为新型化学探针和癌症治疗剂的潜力很大。
Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348 we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from myeloproliferative neoplasm (MPN) patients. Screening across 931 cancer cell lines revealed differential growth inhibitory potential with highest activity against bone and blood cancers, and greatly enhanced activity over the single BET inhibitor JQ1. Gene-drug sensitivity analyses and drug combination studies indicate synergism of BRD4 and kinase inhibition as a plausible reason for the superior potency in cell killing. Combined, our findings indicate promising potential of these agents as novel chemical probes and cancer therapeutics.