Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
14 04 2020
14 04 2020
Historique:
received:
17
09
2019
accepted:
11
02
2020
entrez:
14
4
2020
pubmed:
14
4
2020
medline:
15
5
2021
Statut:
ppublish
Résumé
Internal tandem duplication of FLT3 (FLT3-ITD) is one of the most common somatic mutations in acute myeloid leukemia (AML); it causes constitutive activation of FLT3 kinase and is associated with high relapse rates and poor survival. Small-molecule inhibition of FLT3 represents an attractive therapeutic strategy for this subtype of AML, although resistance from secondary FLT3 tyrosine kinase domain (FLT3-TKD) mutations is an emerging clinical problem. CCT241736 is an orally bioavailable, selective, and potent dual inhibitor of FLT3 and Aurora kinases. FLT3-ITD+ cells with secondary FLT3-TKD mutations have high in vitro relative resistance to the FLT3 inhibitors quizartinib and sorafenib, but not to CCT241736. The mechanism of action of CCT241736 results in significant in vivo efficacy, with inhibition of tumor growth observed in efficacy studies in FLT3-ITD and FLT3-ITD-TKD human tumor xenograft models. The efficacy of CCT241736 was also confirmed in primary samples from AML patients, including those with quizartinib-resistant disease, which induces apoptosis through inhibition of both FLT3 and Aurora kinases. The unique combination of CCT241736 properties based on robust potency, dual selectivity, and significant in vivo activity indicate that CCT241736 is a bona fide clinical drug candidate for FLT3-ITD and TKD AML patients with resistance to current drugs.
Identifiants
pubmed: 32282883
pii: S2473-9529(20)31409-9
doi: 10.1182/bloodadvances.2019000986
pmc: PMC7160287
doi:
Substances chimiques
Benzothiazoles
0
Phenylurea Compounds
0
Protein Kinase Inhibitors
0
quizartinib
7LA4O6Q0D3
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Aurora Kinases
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
1478-1491Subventions
Organisme : Cancer Research UK
ID : C309/A8274
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C309/A11566
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C1178/A10294
Pays : United Kingdom
Informations de copyright
© 2020 by The American Society of Hematology.
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