Reference Detail

Ref Type

Journal Article

PMID

(29187377)

Authors

Yamaura T, Nakatani T, Uda K, Ogura H, Shin W, Kurokawa N, Saito K, Fujikawa N, Date T, Takasaki M, Terada D, Hirai A, Akashi A, Chen F, Adachi Y, Ishikawa Y, Hayakawa F, Hagiwara S, Naoe T, Kiyoi H

Title

A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood	131	4	2018 Jan 25	426-438	Blood

URL

Abstract Text

An activating mutation of Fms-like tyrosine kinase 3 (FLT3) is the most frequent genetic alteration associated with poor prognosis in acute myeloid leukemia (AML). Although many FLT3 inhibitors have been clinically developed, no first-generation inhibitors have demonstrated clinical efficacy by monotherapy, due to poor pharmacokinetics or unfavorable safety profiles possibly associated with low selectivity against FLT3 kinase. Recently, a selective FLT3 inhibitor, quizartinib, demonstrated favorable outcomes in clinical studies. However, several resistant mutations emerged during the disease progression. To overcome these problems, we developed a novel FLT3 inhibitor, FF-10101, designed to possess selective and irreversible FLT3 inhibition. The co-crystal structure of FLT3 protein bound to FF-10101 revealed the formation of a covalent bond between FF-10101 and the cysteine residue at 695 of FLT3. The unique binding brought high selectivity and inhibitory activity against FLT3 kinase. FF-10101 showed potent growth inhibitory effects on human AML cell lines harboring FLT3 internal tandem duplication (FLT3-ITD), MOLM-13, MOLM-14, and MV4-11, and all tested types of mutant FLT3-expressing 32D cells including quizartinib-resistant mutations at D835, Y842, and F691 residues in the FLT3 kinase domain. In mouse subcutaneous implantation models, orally administered FF-10101 showed significant growth inhibitory effect on FLT3-ITD-D835Y- and FLT3-ITD-F691L-expressing 32D cells. Furthermore, FF-10101 potently inhibited growth of primary AML cells harboring either FLT3-ITD or FLT3-D835 mutation in vitro and in vivo. These results indicate that FF-10101 is a promising agent for the treatment of patients with AML with FLT3 mutations, including the activation loop mutations clinically identified as quizartinib-resistant 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
FF-10101	FF-10101	50	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
FF-10101		FF-10101-01\|FF10101\|FF 10101	CSF1R Inhibitor 28 FLT3 Inhibitor 69 KIT Inhibitor 57	FF-10101 is a second generation and irreversible inhibitor of Flt3, including the internal tandem duplication (FLT3-ITD) and known resistance mutations (D835Y, Y842C, Y842H, or F691L) and also inhibits Kit and Csf1r (Fms) (PMID: 29187377, PMID: 32722298)

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
FLT3	C695S	missense	unknown	FLT3 C695S lies within the protein kinase domain of the Flt3 protein (UniProt.org). C695S does not alter kinase activity, dimerization, or phosphorylation of Flt3 or Erk, results in decreased viability, transformation, and Stat5 phosphorylation in the context of FLT3 internal tandem duplication (FLT3-ITD) in cultured cells (PMID: 31606550), and has been demonstrated to confer resistance to some FLT3 inhibitors (PMID: 29187377), but has not been individually characterized and therefore, its effect on Flt3 protein function is unknown.	Y
FLT3	D835V	missense	gain of function	FLT3 D835V lies within the protein kinase domain activation loop of the Flt3 protein (PMID: 11290608). D835V results in constitutive phosphorylation of Flt3 and activation of Stat5, Erk signaling, leading to transformation of cultured cells (PMID: 15256420), and has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 22504184, PMID: 29187377).	Y
FLT3	D835Y	missense	gain of function	FLT3 D835Y lies within the protein kinase domain activation loop of the Flt3 protein (UniProt.org, PMID: 11290608). D835Y results in constitutive phosphorylation of Flt3 and activation of Stat5, Erk signaling, leading to transformation of cultured cells (PMID: 15256420, PMID: 30651561), and has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 22504184, PMID: 29187377).	Y
FLT3	F691L	missense	no effect - predicted	FLT3 F691L lies within the protein kinase domain of the Flt3 protein (PMID: 23430109). F691L has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 23430109, PMID: 19318574, PMID: 22504184, PMID: 29187377), but is not transforming in cell culture (PMID: 30651561), and therefore, is predicted to have no effect on Flt3 protein function.	Y
FLT3	Y842C	missense	gain of function	FLT3 Y842C lies within the protein kinase domain of the Flt3 protein (UniProt.org). Y842C results in constitutive phosphorylation of Flt3, activation of Stat5 signaling, is transforming in cell culture (PMID: 15345593), and has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 22504184, PMID: 29187377).	Y
FLT3	Y842H	missense	gain of function	FLT3 Y842H lies within the protein kinase domain of the Flt3 protein (UniProt.org). Y842H results in increased phosphorylation of Flt3, activation of Stat5 and Mapk, and transformation of cultured cells (PMID: 14604974), and is associated with acquired resistance in the context of FLT3-ITD (PMID: 25847190, PMID: 22504184, PMID: 29187377).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins FLT3 D835Y	acute myeloid leukemia	sensitive	FF-10101	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FF-10101 inhibited Flt3 autophosphorylation and growth of leukemic cell lines and inhibited growth of cell line xenografts with FLT3-ITD/D835Y compound mutations (PMID: 29187377).	29187377
FLT3 exon 14 ins FLT3 Y842H	hematologic cancer	sensitive	FF-10101	Preclinical - Cell culture	Actionable	In a preclinical study, FF-10101, as compared to Quizartinib, inhibited Flt3 autophosphorylation and cell proliferation of transformed 32Dcl3 murine myeloid cells expressing a human FLT3-ITD/Y842H compound mutation (PMID: 29187377).	29187377
FLT3 exon 14 ins FLT3 C695S	hematologic cancer	predicted - resistant	FF-10101	Preclinical - Biochemical	Actionable	In a preclinical study, FF-10101 treatment failed to inhibit Flt3 phosphorylation in transformed human cells expressing FLT3-ITD and FLT3 C695S in culture (PMID: 29187377).	29187377
FLT3 exon 14 ins FLT3 Y842C	hematologic cancer	sensitive	FF-10101	Preclinical - Cell culture	Actionable	In a preclinical study, FF-10101, as compared to Quizartinib, inhibited Flt3 autophosphorylation and cell proliferation of transformed 32Dcl3 murine myeloid cells expressing a human FLT3-ITD/Y842C compound mutation (PMID: 29187377).	29187377
FLT3 exon 14 ins FLT3 D835H	acute myeloid leukemia	sensitive	FF-10101	Preclinical - Pdx	Actionable	In a preclinical study, FF-10101 inhibited cell growth in AML-patient-derived xenograft models with FLT3-ITD/D835H compound mutations (PMID: 29187377).	29187377
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	FF-10101	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, FF-10101 inhibited Flt3 autophosphorylation and cell growth of leukemic cells in culture and in AML-patient-derived xenograft models with FLT3-ITD mutations (PMID: 29187377).	29187377
FLT3 exon 14 ins FLT3 F691L	acute myeloid leukemia	sensitive	FF-10101	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FF-10101 inhibited Flt3 autophosphorylation and growth of leukemic cell lines and inhibited growth of cell line xenografts with FLT3-ITD/F691L compound mutations (PMID: 29187377).	29187377
KIT D816V	hematologic cancer	sensitive	FF-10101	Preclinical - Cell culture	Actionable	In a preclinical study, FF-10101, as compared to Quizartinib, inhibited cell proliferation of transformed 32Dcl3 murine myeloid cells expressing human Kit D816V (PMID: 29187377).	29187377