Targeting AML-associated FLT3 mutations with a type I kinase inhibitor.
Cancer
Drug therapy
Hematology
Leukemias
Oncology
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
01 04 2020
01 04 2020
Historique:
received:
02
02
2019
accepted:
08
01
2020
pubmed:
10
3
2020
medline:
31
12
2020
entrez:
10
3
2020
Statut:
ppublish
Résumé
Tyrosine kinase domain (TKD) mutations contribute to acquired resistance to FMS-like tyrosine kinase 3 (FLT3) inhibitors used to treat FLT3-mutant acute myeloid leukemia (AML). We report a cocrystal structure of FLT3 with a type I inhibitor, NCGC1481, that retained potent binding and activity against FLT3 TKD and gatekeeper mutations. Relative to the current generation of advanced FLT3 inhibitors, NCGC1481 exhibited superior antileukemic activity against the common, clinically relevant FLT3-mutant AML cells in vitro and in vivo.
Identifiants
pubmed: 32149729
pii: 127907
doi: 10.1172/JCI127907
pmc: PMC7108888
doi:
pii:
Substances chimiques
Protein Kinase Inhibitors
0
FLT3 protein, human
EC 2.7.10.1
Flt3 protein, mouse
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2017-2023Subventions
Organisme : NHLBI NIH HHS
ID : R35 HL135787
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211404
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK113639
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM063483
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA217140
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI118697
Pays : United States
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