In complicated three potent compounds for MDM2 plus the very first crystallographic structure of a small-molecule with MDM2 [51]. Within the crystallographic structure the [51]. In the crystallographic structure the (nutlin-2: 1, Figure two) in complicated with MDM2 para-bromophenyl ring at position four occupies Leu26(p53) pocket even though the para-bromophenyl substituent at position 5 inserts deeply into the Trp23(p53) para-bromophenyl ring at position 4 occupies Leu26(p53) pocket although the para-bromophenyl pocket with at position atom enhancing the binding by(p53) pocket using the bromo atom enhancing the substituent the bromo five inserts deeply into the Trp23 filling a small cavity not commonly occupied by the indole ring of p53 Trp23. The not ordinarily occupied by theby the ethyl ether side chain of Phe19(p53) binding by filling a compact cavity Phe19(p53) pocket is occupied indole ring of p53 Trp23. The the third aromatic ring whilst by para-methoxy group mimics the p53 Leu22. The N1 chain functions primarily as pocket is occupied its the ethyl ether side chain in the third aromatic ring whilst its para-methoxy a “solubility-tag” butp53 Leu22. The to activity by possibly mostly as apolar interactions between group mimics the also contributes N1 chain functions establishing “solubility-tag” but in addition the (R)-(+)-Citronellal Metabolic Enzyme/Protease hydroxyl group and Gln72 side establishing polar interactions among the hydroxyl group and contributes to activity by possibly chain [51,52]. Probably the most potent compound identified was the enantiopure nutlin-3a (2, SPR IC50 = 0.09 , Gln72 side chain [51,52]. MTTThe most potent compound p53 cancerwas the enantiopure nutlin-3a (two,in monotherapy , IC50 = 1 in wild-type identified cell lines), which has been utilized SPR IC50 = 0.09 and in combination in wild-type p53 cancer cell lines), which has been utilised in monotherapynutlins MTT IC50 = 1 with other anti-cancer drugs and radiation, serving as proof-of-concept for and in and to establish p53-MDM2 interaction as a promising and useful target [538]. for nutlins and combination with other anti-cancer drugs and radiation, serving as proof-of-concept Nonetheless, the biological and pharmacokinetic (PK) properties of nutlin-3a have been suboptimal for clinicalHowever, the to establish p53-MDM2 interaction as a promising and important target [538]. development. The optimizationpharmacokinetic (PK) properties of nutlin-3a had been suboptimal for clinical biological and of those properties was primarily focused on probing unique N1 side chains to improve PK properties and MDM2 binding and on removing stability liabilities located in the earlier development. The optimization of these properties was mainly focused on probing diverse N1 side compounds (oxidation properties and MDM2 binding and on removing stability liabilities discovered in chains to boost PK in the major core to imidazole, and metabolization with the para-methoxyphenyl group to phenol). The PK properties have been amendedcoreadding methyl groups to positions four from the the earlier compounds (oxidation on the key by to imidazole, and metabolization and five from the imidazoline ring, andto phenol). The PK properties were amended by addingOne with the finest para-methoxyphenyl group by replacing the methoxy having a tert-butyl group [59]. methyl groups compounds, four and five of the imidazoline ring, and by replacing the methoxy using a tert-butyl group to positions RG7112 (three, HTRF IC50 = 18 nM, MTT IC50 = 0.18.2 in wild-type p53 cancer cell lines) One of many besttrials [60]. RG7112 shows excellent selectivi.