Journal: Endocrine-Related Cancer

Article Title: Inhibition of GATA2 in prostate cancer by a clinically available small molecule

doi: 10.1530/ERC-21-0085

Figure Lengend Snippet: (A) Dilazep suppresses the c-MYC transcriptional program. Using GSEA, we compared our signatures of dilazep treatment in our three PC cell lines against publicly available prostate-specific signatures of c-MYC activity. We found that the gene programs induced by c-MYC are strongly suppressed by dilazep in all three cell lines for, while genes suppressed by c-MYC are strongly induced by dilazep. These results demonstrate that dilazep potently suppresses c-MYC activity in PC cells. All P < 0.001. (B) The dilazep transcriptional program correlates with decreased GATA2 activity score, AR activity score, and c-MYC activity score in PC patient cohorts. We applied the gene signature derived from our treatment of LNCaP cells with dilazep, as well as the previously published footprints of GATA2 (GSE63539 and He et al. 2014 ), AR (GSE63539 and He et al. 2014 ) and c-MYC (two signatures, one from overexpression of c-MYC for 12 hrs in LNCaP cells (GSE51384 and Barfeld et al. 2015 ) and the other from knockdown of c-MYC via siRNA in LNCaP ( Koh et al. 2011 )), and computed an activity score for each specimen in multiple previously reported human PC specimen cohorts: Taylor et al. (2010) , Cai et al. (2013) , and the Cancer Genome Atlas (TCGA) ( https://doi.org/10.1530/ERC-21-0085 .

Article Snippet: Thus, we screened for alternative, structurally related compounds in silico , using the SuperPred algorithm ( http://prediction.charite.de/ ) ( Nickel et al. 2014 ) and identified dilazep (C 31 H 44 N 2 O 11 , MW 604.7 g/mol), a vasodilator, as a clinically available drug with potential inhibitory activity against GATA2 (Supplementary Fig. 1).

Techniques: Activity Assay, Derivative Assay, Over Expression, Knockdown

Journal: Purinergic Signalling

Article Title: Exploring novel dilazep derivatives as hENT1 inhibitors and potentially covalent molecular tools

doi: 10.1007/s11302-024-10026-x

Figure Lengend Snippet: Chemical structures of reported hENT1 (therapeutic) inhibitors dipyridamole and dilazep, and molecular tools NBTI, draflazine and ST7092 and their corresponding K i values. K i values are as previously described, with the exception of ST7092 (data unpublished)

Article Snippet: Dilazep and ST7092 were obtained from ASTA-Werke AG (Bielefeld, Germany) and Chemie Linz AG (Linz, Austria), respectively.

Techniques:

Journal: Purinergic Signalling

Article Title: Exploring novel dilazep derivatives as hENT1 inhibitors and potentially covalent molecular tools

doi: 10.1007/s11302-024-10026-x

Figure Lengend Snippet: Binding poses of dilazep piperazine analogs with decreasing number of methoxy substitutions including their docking scores. hENT1 PDB: 6OB7 (grey) with (re)docked dilazep and co-crystallized structure inhibitor in a thin line for reference (a), ST7092 (b), 6m (c), and 6n (d). Polar contacts (hydrogen bonds) are represented as dashed yellow lines. Target nucleophilic residue C439 (TM2) is colored in orange for reference

Article Snippet: Dilazep and ST7092 were obtained from ASTA-Werke AG (Bielefeld, Germany) and Chemie Linz AG (Linz, Austria), respectively.

Techniques: Binding Assay, Residue