Ivity in a xenograft model at doses that happen to be inactive in monotherapy doxorubicin-mediated in vivo activity in a xenograft model at doses which might be inactive in monotherapy treatment [76]. therapy [76]. More lately, two new scaffolds determined by the principle of bioisosterism of BDP have already been bioisosterism of BDP have been Additional recently, two new scaffolds determined by the principle reported: 1,4 thienodiazepine-2,5-diones (TDZ) [77] and thiobenzodiazepines (Trometamol site Figure 4) [78,79]. For thienodiazepine-2,5-diones (TDZ) [77] and thiobenzodiazepines (Figure 4) [78,79]. reported: For TDZ only a cell-free binding screening has reported, from which compound 10 emerged as lead TDZ only a cell-free binding screening has been been reported, from which compound ten emerged as lead compound awith aKi of 40 40 [77]. The synthesis andbiological evaluation of FP Ki of [77]. The synthesis and biological evaluation of compound with FP thiobenzo-diazepines showed that the very simple replacement of the oxygen by a sulfur atom increased the oxygen by a sulfur atom elevated thiobenzo-diazepines showed that the uncomplicated the potency inside a FP binding assay, but not in GSK726701A Epigenetic Reader Domain cell-based evaluation. In In this SAR study compound assay, but not in cell-based evaluation. this SAR study compound 11 the potency in a FP 11 emerged as a prospective lead compound for future optimization with a FP Ki of 5.34 and MTT emerged as a possible lead compound for future optimization with a FP Ki of five.34 and MTT U-2OS IC50 of 1.06 [78]. Continuation U-2OS IC50 of 1.06 [78]. Continuation of this operate resulted in compounds with improved affinity to operate resulted in compounds with improved affinity to MDM2, but with no cell-based assay improvement [79]. Additional not too long ago, new benzodiazepine MDM2, but with out cell-based assay improvement [79]. Additional not too long ago, new benzodiazepine analogues analogues were reported, but once again without the need of displaying potency improvement (the very best derivative, FP have been reported, but once more with out displaying potency improvement (the ideal derivative, 12, has12, has FP Ki = MTT U-2OS IC50 = 3.12 ) [80]. Additionally, these new scaffold derivatives did Ki = 0.two , 0.2 , MTT U-2OS IC50 = 3.12 ) [80]. Additionally, these newscaffold derivatives didn’t show selectivity toward cells with wild-type p53 as observed 1,4-benzodiazepine-2,5-dione not show selectivity toward cells with wild-type p53 as observed for 1,4-benzodiazepine-2,5-dione derivatives (e.g., compound 9 is ten instances much more selective, MCF-7 derivatives (e.g., compound 9 is 10 occasions more selective, MCF-7 vs. MDA-MB-231 [75]). MDA-MB-231 [75]).Figure four. Examples of Figure 4. Examples of benzodiazepinedione derivatizations. derivatizations.Hardcastle et al. described inhibitors on the p53-MDM2 interaction determined by an isoindolinone Hardcastle et al. described inhibitors of the p53-MDM2 interaction determined by an isoindolinone scaffold.Compounds bearing this template (13a,b, Figure five) have been first identified as modest inhibitors scaffold. Compounds bearing this template (13a,b, Figure 5) had been first identified as modest inhibitors in the p53-MDM2 interaction (IC50 200 ) in an in vitro p53-MDM2 binding study. on the p53-MDM2 interaction (IC50 200 ) in an in vitro p53-MDM2 binding assay screeningassay screening study. Inside a a modest compound library focused around the isoindolinone core was synthesized Within a very first optimization,very first optimization, a modest compound library focused on the isoindolinone core was synthesized guided by in silico the published.
