The AKT kinase, also known as protein kinase B or PKB, is a serine-threonine kinase that phosphorylates other proteins and molecules that act as second messengers, which are involved involved in important cellular processes, such as cell proliferation and growth, signaling, absorption and metabolism of glucose. AKT is frequently amplified and over-expressed in human cancer cells, therefore its inhibition is an atractive therapeutic target in anticancer drug development. There are three known subtypes, AKT-1, AKT-2 and AKT-3. Each subtype is associated with different types of cancers. In particular, AKT-2 is amplified in pancreatic, breast and ovarian tumors. AKT-3 is over expressed in breast and prostate cancers, the presence of AKT-1 in tumors is less common. Small molecules targeting the ATP-binding site have been reported; however, it is important to study the factors that determine the selectivity of these inhibitors in each subtype of AKT, also to determine the factors that favor the multitarget activity.Herein, we present a systematic characterization of the SAR of 50 compounds screened against the three AKT subtypes. The activity landscape across multiple AKT subtypes was characterized using the dual and triple activity difference (DAD/TAD) maps. We also employed SAS maps to systematically identify and analyze the activity cliff generators present in the dataset. Analysis of pairs of compounds with high structure similarity revealed the presence of single-, dual, and pan-receptor activity cliffs. Moreover, single-target and dual-target activity cliff generators for AKT-1/AKT-2, AKT-2/AKT-3 and AKT-1/AKT-3 were identified. In addition, docking studies were performed with the compounds that were classified as cliff generators in order to analyze the factors that are involved in the ligand-enzyme interactions. The analysis of the chemical structures in this work points to specific structural features that are helpful for the design of new AKT inhibitors.

Activity landscape modeling of AKT/PKB inhibitors

248th National Meeting (2014)

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