Drug-like Properties Investigation Of Novel Hit Compounds With Anti-cancer Effect

Poor ADME/Tox properties are one of the main reasons for drug R&D project closure.To seek the balance between the pharmacokinetics and pharmacodynamics,researchers have developed the assays for drug-like property evaluation.In this study,a series of drug-like property assessments including lipophilicity,in vitro metabolism stability and in vivo pharmacokinetics were established and applied to the hit compounds with anti-cancer effects.According to the RP-HPLC-based lipophilicity evaluation,most of the hit compounds targeting STAT3 and EP4 enjoyed moderate lipophilicity at pH 7.4,while others had relatively high lipophilicity.For the phase ? metabolism stability evaluation,hit compounds targeting Myoferlin was not stable in rat liver microsome,and other compounds had differentiated metabolite stabilities within the groups.Compounds targeting EP4 and BCL-6 were stable in human liver microsome.The microsome stability of tested compounds were either correlated or uncorrelated with their lipophilicity,which should be considered together with their chemical structures.In the rodent pharmacokinetic assay,the intravenous half-life of STAT3-targeting compound WB-460 was short,which was inconsistent with its moderate lipophilicity and high metabolism stability.Compounds targeting EP4 exhibited balanced pharmacokinetic properties generally.Different compounds targeting BCL6 showed dissimilar pharmacokinetic behaviors in mice.Due to high lipophilicity,compounds targeting BCL-6 had high elimination rates and large volumes of distribution in mice.In summary,the present study developed evaluation methods of lipophilicity,in vitro metabolite stability and in vivo pharmacokinetics for the in-house synthesized hit compounds with antineoplastic properties.The three sections of this work provided significant indexes of pharmacokinetics-based compound ranking in early drug discovery stage.The conclusions verified and replenished each other,and provided the guidance for drug development.