Promoted tumor regression in a SJSA-1 xenograft tumor model [123]. Hence, further optimization was pursued.pursued. The co-crystal a SJSA-1 xenograft tumor model [123]. As a result, further optimization was The co-crystal structure of 52 with 52 with MDM2 showed a hydrophobic cleft near Phe19(p53) pocket that may be filled in structure ofMDM2 showed a shallow shallow hydrophobic cleft near Phe19(p53) pocket that may very well be order to improve binding. As a result, a number of derivatives have been synthesized containing distinct filled to be able to improve binding. Thus, numerous derivatives had been synthesizedcontaining various N-side chains [124], major the really potent sulfonamide piperidone 53 (HTRF IC50 IC50 = nM, nM, N-side chains [124], major toto the very potent sulfonamide piperidone 53 (HTRF = 0.0910.091 EdU EdU SJSA-1 0.48 0.48 nM, Figure 14) Nonetheless, the sulfonamides proved less metabolically stable SJSA-1 IC50 =IC50 =nM, Figure 14) [125]. [125]. However, the sulfonamides proved less metabolically steady than 52. Further optimizations led to compound 54 (HTRF IC50 nM, EdU SJSA-1 IC50 = 350 = 3 than 52. Further optimizations led to compound 54 (HTRF IC50 = 0.1 = 0.1 nM, EdU SJSA-1 IC nM, nM, Figure 13) compound AMG232 (55, HTRF IC IC50 = 0.six nM, EdU SJSA-1 IC = 9.1 nM) [124]. Figure 13) and and compound AMG232 (55, HTRF50 = 0.six nM, EdU SJSA-1 IC5050= 9.1 nM) [124]. Neverthelessitit is noteworthy point out that even aeven a N-groupN-group rise to potent derivatives Nevertheless is noteworthy to to point out that Aurintricarboxylic acid References straightforward very simple can give can give rise to potent derivatives (56, 9 nM, IC50 SJSA-1 EdU 0.38 , Figure 14) [126]. Compound 55 Compound 55 (56, HTRF IC50 =HTRF EdU = 9 nM,IC50 = SJSA-1 IC50 = 0.38 , Figure 14) [126].entered clinical entered clinical trials in compound 54 compound 54 was more it presented poorer PK properties in trials in 2012. Although2012. Although was much more active than 55 active than 55 it supplied poorer PK properties in in in vivo research. vivo research.Figure 14. Piperidinone and morpholinone derivatives. lower quadrant: structure of Figure 14. Piperidinone and morpholinone derivatives. Correct lower quadrant: crystal structure of compound 54 bound to MDM2 (PDB 4OAS). MDM2 surface is colored in blue for hydrophilic regions compound 54 bound to MDM2 (PDB 4OAS). MDM2 surface is colored in blue for hydrophilic areas and grey for hydrophobic locations. Compound 54 is depicted in stick model and is colored as outlined by and grey for hydrophobic areas. Compound 54 is depicted in stick model and is colored according to element form: white for carbon atoms, blue for the nitrogen atom, red for for oxygen atoms, yellow the element sort: white for carbon atoms, blue for the nitrogen atom, red oxygen atoms, yellow for for sulfur atom, and and greenchlorine atoms. the sulfur atom, green for for chlorine atoms.Binding of 55 with MDM2 was extrapolated in the co-crystal structure of 54 with MDM2 Binding of 55 with MDM2 was extrapolated in the co-crystal structure of 54 with MDM2 (Figure 14). As anticipated 3 pivotal p53 p53 amino acids Trp23 Trp23 and Leu26 mirrored (Figure 14). As expected thethe three pivotal amino acids Phe19,Phe19, and Leu26 are beingare becoming mirrored by the isopropyl, C6 aryl group aryl group, respectively. Two substituents interact with by the isopropyl, C6 aryl group and C5 and C5 aryl group, respectively. Two substituents interact with His96: the C5 aryl engages in stacking, while the carboxylate functio.
