A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity.
Adenosine Triphosphate
/ metabolism
Allosteric Regulation
Cell Line, Tumor
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
HT29 Cells
Humans
Models, Molecular
Mutation
Phosphoproteins
/ chemistry
Protein Conformation
Protein Kinase Inhibitors
/ chemistry
Proto-Oncogene Proteins c-akt
/ antagonists & inhibitors
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
10
09
2019
accepted:
24
04
2020
revised:
07
04
2020
pubmed:
23
5
2020
medline:
26
2
2021
entrez:
23
5
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32439931
doi: 10.1038/s41416-020-0889-4
pii: 10.1038/s41416-020-0889-4
pmc: PMC7435276
doi:
Substances chimiques
Phosphoproteins
0
Protein Kinase Inhibitors
0
Adenosine Triphosphate
8L70Q75FXE
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
542-555Subventions
Organisme : Cancer Research UK (CRUK)
ID : A21773
Organisme : Cancer Research UK (CRUK)
ID : CRC553X
Organisme : Cancer Research UK (CRUK)
ID : C16420/A18066
Organisme : Cancer Research UK (CRUK)
ID : C1060/A16464
Organisme : RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)
ID : BB/M006174/1
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