Ty18 nM, MTT IC50 = 0.18.2 in [59]. entered clinical compounds, RG7112 (3, HTRF IC50 = over mutated p53 cancer cells (MTT IC50 = five.70.three ), and it’s in a position to activate the p53trials [60]. pathway in wild-type p53 cells, top wild-type p53 cancer cell lines) entered clinical signaling RG7112 shows very good selectivity over to cell cycle arrest and apoptosis.IC50 = five.70.3a ), and it truly is in a position to activate the p53 signaling mutated p53 cancer cells (MTT Furthermore every day dose of one hundred mg/kg is capable of advertising partly regression of SJSA-1 cells,MHM tumor xenograft mice models [46,61]. pathway in wild-type p53 and top to cell cycle arrest and apoptosis. Furthermore a daily dose Hu et al. is capable of promoting partly regression of SJSA-1 and MHM tumor varying the N1 of 100 mg/kg reported novel derivatives based on the imidazoline scaffold, mostly by xenograft mice side chain of nutlin-3. Compound 4 (FP IC50 = 0.59 , MTT HCT116 p53+/+ IC50 = 3.73 , Figure two) models [46,61]. was one et al reportedpotentderivatives based on thealthough notscaffold, mainly by varying the N1 Hu of the most novel compounds obtained, imidazoline representing an improvement of potency whennutlin-3. Compound 4 (FP Nevertheless, these research helped+/+ IC50 = 3.73 , altering side chain of compared with nutlin-3a. IC50 = 0.59 , MTT HCT116 p53 establishing that Figure two) N1 side chain interferes mainly with PK properties butalthough not representingSeveral other analogs was one of the most potent compounds obtained, also with potency [62,63]. an improvement of potency when compared with nutlin-3a. Nevertheless, these studies helped establishing thatPharmaceuticals 2016, 25 Pharmaceuticals 2016, 9,9,5 ofof 33 5changing N1 side chain interferes primarily with PK properties but additionally with potency [62,63]. A number of are disclosed inare disclosed in patents from Hoffman-La Roche, presenting exactly the same imidazoline other analogs patents from Hoffman-La Roche, presenting the exact same imidazoline core and also other BMP-2 Inhibitors Related Products structure variations including imidazopyridinones [30,39,64,65]. In addition, Miyazaki et al. also published core and also other structure variations including imidazopyridinones [30,39,64,65]. Additionally, Miyazaki et a al also published a new series of dihydroimidazothiazole derivatives structure, which include DS-5272 new series of dihydroimidazothiazole derivatives based on the nutlin-3a according to the nutlin-3a (5, HTRF IC50 = 2.4DS-5272 (5, HTRF IC50 50 2.40.2 ) [66,67]. structure, for instance , LCVA SJSA-1 IC = = , LCVA SJSA-1 IC50 = 0.2 ) [66,67]. The screening a a library of 338.000 compounds working with a miniaturized affinity-based termed The screening of of library of 338.000 compounds working with a miniaturized affinity-based assay, assay, termed ThermoFluor, the 1,4-benzodiazepine-2,5-dione scaffold (BDP) [68]. Chosen compounds ThermoFluor, Pde5 Inhibitors Reagents identified identified the 1,4-benzodiazepine-2,5-dione scaffold (BDP) [68]. Chosen compounds screen were further have been employing a employing fluorescence polarization (FP) from this firstfrom this 1st screentested additional testedfluorescenceapolarization (FP) assay to detect assay p53-MDM2 interaction inhibitors. specificto detect particular p53-MDM2 interaction inhibitors.Figure Nutlin scaffold optimization examples of nutlin derivatizations. Right upper quadrant: Figure two.two. Nutlinscaffold optimization and examples of nutlin derivatizations. Proper upper quadrant: crystal structure of compound three bound crystal structure of compound three bound to MDM2 (PDB 4IPF.
