2. Academic Validation
  3. A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity

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

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. igor.vivanco@icr.ac.uk.
  • # 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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