1207188-38-2Relevant articles and documents
Discovery of a Small-Molecule Bromodomain-Containing Protein 4 (BRD4) Inhibitor That Induces AMP-Activated Protein Kinase-Modulated Autophagy-Associated Cell Death in Breast Cancer
Ouyang, Liang,Zhang, Lan,Liu, Jie,Fu, Leilei,Yao, Dahong,Zhao, Yuqian,Zhang, Shouyue,Wang, Guan,He, Gu,Liu, Bo
, p. 9990 - 10012 (2017/12/15)
Upon the basis of The Cancer Genome Atlas (TCGA) data set, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) were remarkably downregulated in breast cancer. Combined with coimmunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of the pharmacophore and WPF interaction optimization, we designed a small-molecule inhibitor of BRD4, 9f (FL-411) which was validated by cocrystal structure with BD1 of BRD4. Subsequently, 9f was discovered to induce ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction and thus activating AMPK-mTOR-ULK1-modulated autophagic pathway in breast cancer cells. Interestingly, the iTRAQ-based proteomics analyses revealed that 9f induced ACD pathways involved in HMGB1, VDAC1/2, and eEF2. Moreover, 9f displayed a therapeutic potential on both breast cancer xenograft mouse and zebrafish models. Together, these results demonstrate that a novel small-molecule inhibitor of BRD4 induces BRD4-AMPK-modulated ACD in breast cancer, which may provide a candidate drug for future cancer therapy.
Discovery of novel fibroblast growth factor receptor 1 kinase inhibitors by structure-based virtual screening
Ravindranathan, Krishna P.,Mandiyan, Valsan,Ekkati, Anil R.,Bae, Jae H.,Schlessinger, Joseph,Jorgensen, William L.
supporting information; experimental part, p. 1662 - 1672 (2010/07/04)
Fibroblast growth factors (FGFs) play important roles in embryonic development, angiogenesis, wound healing, and cell, proliferation and differentiation. In search, of inhibitors of FGFRl kinase, 2.2 million compounds were docked into the ATP binding site of the protein. A co-crystal structure, which shows two alternative conformations for the nucleotide binding loop, is reported. Docking was performed on both conformations and, ultimately, 23 diverse compounds were purchased and assayed. Following hit validation, two compounds 10 and, 16, a benzylidene derivative of pseudothiohydantoin and a thienopyrimidinone derivative, respectively, were discovered that, inhibit FGFRl kinase with IC50 values of 23 and 50 μM. Initial optimization of 16 led to the more unsaturated, 40, which has significantly enhanced potency, 1.9 μM., The core structures represent new structural motifs for FGFRl, kinase inhibitors. The study also illustrates complexities associated with the choice of protein structures for docking, possible use of multiple kinase structures to seek, selectivity, and hit identification.
