Journal Article

A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity

Palaskas, Nicolaos, Yu, Yi, Raynaud, Florence, Yandim, Cihangir, Lazaro, Glorianne, Chung, Yuen-Li, Casado, Pedro, Schwartz, Brian, Heuss, Sara Farrah, Cutillas, Pedro R., Kaserer, Teresa, Vivanco, Igor, Hayes, Angela, Kostaras, Eleftherios, Hussain, Aasia

2020

Overview

Background AKT, a critical effector of the phosphoinositide 3-kinase (PI3K) signalling cascade, is an intensely pursued therapeutic target in oncology. Two distinct classes of AKT inhibitors have been in clinical development, ATP-competitive and allosteric. Class-specific differences in drug activity are likely the result of differential structural and conformational requirements governing efficient target binding, which ultimately determine isoform-specific potency, selectivity profiles and activity against clinically relevant AKT mutant variants. Methods We have carried out a systematic evaluation of clinical AKT inhibitors using in vitro pharmacology, molecular profiling and biochemical assays together with structural modelling to better understand the context of drug-specific and drug-class-specific cell-killing activity. Results Our data demonstrate clear differences between ATP-competitive and allosteric AKT inhibitors, including differential effects on non-catalytic activity as measured by a novel functional readout. Surprisingly, we found that some mutations can cause drug resistance in an isoform-selective manner despite high structural conservation across AKT isoforms. Finally, we have derived drug-class-specific phosphoproteomic signatures and used them to identify effective drug combinations. Conclusions These findings illustrate the utility of individual AKT inhibitors, both as drugs and as chemical probes, and the benefit of AKT inhibitor pharmacological diversity in providing a repertoire of context-specific therapeutic options.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 1-Phosphatidylinositol 3-kinase / 631/67/1059/153 / 631/67/1059/2326 / 631/67/395 / 631/80/86 / Adenosine Triphosphate - metabolism / AKT protein / Allosteric properties / Allosteric Regulation / Biological activity / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell Line, Tumor / Drug development / Drug Resistance / Drug Resistance, Neoplasm / Drug Screening Assays, Antitumor / Epidemiology / HT29 Cells / Humans / Isoforms / Models, Molecular / Molecular Medicine / Mutation / Oncology / Phosphoproteins - chemistry / Phosphoproteins - metabolism / Protein Conformation / Protein Kinase Inhibitors - chemistry / Protein Kinase Inhibitors - pharmacology / Proto-Oncogene Proteins c-akt - antagonists & inhibitors / Proto-Oncogene Proteins c-akt - chemistry / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Therapeutic targets