Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736.
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Date
2020-04-14ICR Author
Author
Moore, AS
Faisal, A
Mak, GWY
Miraki-Moud, F
Bavetsias, V
Valenti, M
Box, G
Hallsworth, A
de Haven Brandon, A
Xavier, CPR
Stronge, R
Pearson, ADJ
Blagg, J
Raynaud, FI
Chopra, R
Eccles, SA
Taussig, DC
Linardopoulos, S
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Research team
Drug Target Discovery
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Acute Leukaemia
Language
eng
Date accepted
2020-02-11
License start date
2020-04
Citation
Blood advances, 2020, 4 (7), pp. 1478 - 1491
Publisher
ELSEVIER