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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 Theranostics
Vol 11
Issue 1
Date 2021
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
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
LT-171-861 FLT3 Inhibitor 55 LT-171-861 is a potent inhibitor of FLT3 with activity against FLT3-ITD, potentially resulting in decreased tumor growth (PMID: 33391463).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 hematologic cells expressing FLT3 D835Y in culture (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 hematologic 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 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 hematologic cells expressing a FLT3-ITD mutation in culture (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 hematologic 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 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 hematologic cells expressing a FLT3-ITD mutation and FLT3 Y842C in culture (PMID: 33391463). 33391463
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 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 hematologic cells expressing a FLT3-ITD mutation and FLT3 D835Y in culture (PMID: 33391463). 33391463