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Ref Type

Journal Article

PMID

(33391463)

Authors

Yu Z, Du J, Hui H, Kan S, Huo T, Zhao K, Wu T, Guo Q, Lu N

Title

LT-171-861, a novel FLT3 inhibitor, shows excellent preclinical efficacy for the treatment of FLT3 mutant acute myeloid leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Theranostics	11	1	2021	93-106	Theranostics

URL

Abstract Text

Rationale: Acute myeloid leukemia (AML) is a common type of haematological malignancy. Several studies have shown that neoplasia in AML is enhanced by tyrosine kinase pathways. Recently, given that aberrant activation of Fms-like tyrosine receptor kinase 3 (FLT3) acts as a critical survival signal for cancer cells in 20‒30% patients with AML, inhibition of FLT3 may be a potential therapeutic strategy. Therefore, we identified LT-171-861, a novel kinase inhibitor with remarkable inhibitory activity against FLT3, in preclinical models of AML. Methods: We determined the inhibitory effects of LT-171-861 in vitro using AML cell lines and transformed BaF3 cells. Target engagement assays were used to verify the interaction between LT-171-861 and FLT3. Finally, a subcutaneous model and a bone marrow engrafted model were used to evaluate the antitumor effects of LT‑171‑861 in vivo. Results: Our data demonstrated that LT-171-861 had high affinity for FLT3 protein. We also showed that LT-171-861 had an inhibitory effect on FLT3 mutants in cellular assays. Moreover, LT-171-861 had a growth-inhibitory effect on human AML cell lines harboring FLT3 internal tandem duplications (FLT3-ITD) such as FLT3-D835Y, FLT3‑ITD-N676D, FLT3-ITD-D835Y, FLT3-ITD-F691L, FLT3-ITD-Y842C and AML blasts from patients with FLT3-ITD. Furthermore, LT-171-861 showed potent antileukemic efficacy against AML cells. We also show the efficacy of LT‑171-861 in a subcutaneous implantation model and a bone marrow engrafted model in vivo, where administration of LT-171-861 led to almost complete tumor regression and increased survival. Conclusions: Overall, this study not only identifies LT-171-861 as a potent FLT3 inhibitor, but also provides a rationale for the upcoming clinical trial of LT-171-861 in patients with AML and FLT3-ITD mutations.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
LT-171-861	LT-171-861	7	0

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
LT-171-861			FLT3 Inhibitor 69	LT-171-861 inhibits FLT3 with activity against FLT3-ITD, as well as PIM2, potentially resulting in decreased tumor growth (PMID: 33391463, PMID: 34111425).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	LT-171-861	Preclinical - Cell line xenograft	Actionable	In a preclinical study, LT-171-861 inhibited cell growth, decreased FLT3 signaling, and induced apoptosis in acute myeloid leukemia cell lines and primary patient-derived peripheral blood mononuclear cells harboring FLT3-ITD mutations in culture, and resulted in tumor regression and prolonged survival in cell line xenograft models (PMID: 33391463).	33391463
FLT3 exon 14 ins FLT3 F691L	hematologic cancer	sensitive	LT-171-861	Preclinical - Cell line xenograft	Actionable	In a preclinical study, LT-171-861 inhibited cell viability and decreased FLT3 phosphorylation in transformed cells expressing a FLT3-ITD mutation and FLT3 F691L in culture, and inhibited tumor growth and prolonged survival in cell line xenograft models (PMID: 33391463).	33391463
FLT3 exon 14 ins FLT3 N676D	hematologic cancer	sensitive	LT-171-861	Preclinical - Cell line xenograft	Actionable	In a preclinical study, LT-171-861 inhibited cell viability and decreased FLT3 phosphorylation in transformed cells expressing a FLT3-ITD mutation and FLT3 N676D in culture, and inhibited tumor growth and prolonged survival in cell line xenograft models (PMID: 33391463).	33391463
FLT3 D835Y	hematologic cancer	sensitive	LT-171-861	Preclinical - Cell culture	Actionable	In a preclinical study, LT-171-861 inhibited cell viability and decreased FLT3 phosphorylation in transformed cells expressing FLT3 D835Y in culture (PMID: 33391463).	33391463
FLT3 exon 14 ins	hematologic cancer	sensitive	LT-171-861	Preclinical - Cell culture	Actionable	In a preclinical study, LT-171-861 inhibited cell viability and decreased FLT3 phosphorylation in transformed cells expressing a FLT3-ITD mutation in culture (PMID: 33391463).	33391463
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Cytarabine + LT-171-861	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of LT-171-861 and Cytosar-U (cytarabine) synergistically inhibited cell viability in acute myeloid leukemia cell lines harboring FLT3-ITD mutations in culture (PMID: 33391463).	33391463
FLT3 exon 14 ins FLT3 D835Y	hematologic cancer	predicted - sensitive	LT-171-861	Preclinical - Cell culture	Actionable	In a preclinical study, LT-171-861 inhibited cell viability and decreased FLT3 phosphorylation in transformed cells expressing a FLT3-ITD mutation and FLT3 D835Y in culture (PMID: 33391463).	33391463
FLT3 exon 14 ins FLT3 Y842C	hematologic cancer	sensitive	LT-171-861	Preclinical - Cell culture	Actionable	In a preclinical study, LT-171-861 inhibited cell viability and decreased FLT3 phosphorylation in transformed cells expressing a FLT3-ITD mutation and FLT3 Y842C in culture (PMID: 33391463).	33391463

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