Ember Stuart W, Lambert Que T, Berndt Norbert, Gunawan Steven, Ayaz Muhammad, Tauro Marilena, Zhu Jin-Yi, Cranfill Paula J, Greninger Patricia, Lynch Conor C, Benes Cyril H, Lawrence Harshani R, Reuther Gary W, Lawrence Nicholas J, Schönbrunn Ernst
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida.
Tumor Biology Department, Moffitt Cancer Center, Tampa, Florida.
Mol Cancer Ther. 2017 Jun;16(6):1054-1067. doi: 10.1158/1535-7163.MCT-16-0568-T. Epub 2017 Mar 23.
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 patients with myeloproliferative neoplasm. 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. .
激酶和BET溴结构域抑制剂在细胞杀伤中的协同作用已在多种癌症中被报道。利用JAK2抑制剂TG101348的化学骨架，我们开发并表征了能有效且同时抑制BRD4和一组特定致癌酪氨酸激酶（包括JAK2、FLT3、RET和ROS1）的单一药物。先导化合物在几种血液癌细胞系中显示出靶向抑制作用，并且在抑制骨髓增殖性肿瘤患者的造血祖细胞生长方面非常有效。对931个癌细胞系的筛选揭示了不同的生长抑制潜力，对骨癌和血癌的活性最高，且比单一的BET抑制剂JQ1活性大大增强。基因药物敏感性分析和药物联合研究表明，BRD4抑制和激酶抑制的协同作用是细胞杀伤中效力更强的一个合理原因。综合来看，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药物具有广阔的前景。
