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

  • Br J Cancer. 2020 Aug;123(4):542-555. doi: 10.1038/s41416-020-0889-4.
Eleftherios Kostaras   #  1 ,  Teresa Kaserer   #  2  3 ,  Glorianne Lazaro  1 ,  Sara Farrah Heuss  1 ,  Aasia Hussain  1 ,  Pedro Casado  4 ,  Angela Hayes  2 ,  Cihangir Yandim  1  5 ,  Nicolaos Palaskas  6 ,  Yi Yu  7 ,  Brian Schwartz  7 ,  Florence Raynaud  2 ,  Yuen-Li Chung  8 ,  Pedro R Cutillas  4 ,  Igor Vivanco  9
Affiliations
  • 1. Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, SM2 5NG, London, UK.
  • 2. Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, SW7 3RP, UK.
  • 3. Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, A-6020, Austria.
  • 4. Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
  • 5. Department of Genetics and Bioengineering, Faculty of Engineering, Izmir University of Economics, 35330, Balçova, Izmir, Turkey.
  • 6. Division of Hematology and Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 7. ArQule, Inc. (a wholly-owned subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA), Burlington, MA, 01803, USA.
  • 8. Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, London, SW7 3RP, UK.
  • 9. Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, SM2 5NG, London, UK. [email protected].
  • # Contributed equally.
PMID: 32439931 DOI: 10.1038/s41416-020-0889-4
Abstract

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.

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