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Abstract

PMID

Authors

Inhwan Bae; Jaeyul Choi; Jiyoung Song; Joo-Yun Byun; Eunyoung Lee; Taehun Song; Yu-Yon Kim; Yesol Bak; Young Hoon Kim; Young Gil Ahn; Kwee Hyun Suh

Title

Abstract 1257: HM43239, a novel FLT3 inhibitor, has the potential to inhibit mutations resistant to FLT3 inhibitors

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	81	13_Supplement	July 1, 2021

URL

https://aacrjournals.org/cancerres/article/81/13_Supplement/1257/667114/Abstract-1257-HM43239-a-novel-FLT3-inhibitor-has

Abstract Text

Acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutations is associated with poor prognosis with a high risk of relapse after therapy and reduces overall survival. Approximately 30 % of AML patients carry FLT3 internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutations. Sustained FLT3 inhibition can result in the emergence of resistance-conferring genetic alteration in TKD domain, usually at residues D835 and F691. Therefore, acquired TKD mutations has become a critical therapeutic target in AML therapy. On the other hand, SYK is one of kinases deeply implicated in many hematologic malignancies and highly activated in FLT3 mutation AML. SYK overexpression is known to promote over transformation of FLT3 driven AML and induce resistance to FLT3 targeted therapy. In this study, we characterized HM43239, a novel FLT3 inhibitor with SYK inhibitory activity, and assessed its potential as a novel therapeutic agent to overcome the resistances against AML therapy using current FLT3 inhibitors. HM43239 is an orally active small molecule inhibitor and it exhibited sub-nanomolar potency on binding affinity for FLT3 wild type, ITD, TKDs and ITD/TKDs mutants. HM43239 potently inhibited phosphorylation of FLT3 and its downstream such as p-STAT3/p-STAT5 dose dependently in both MOLM-14 cells harboring FLT3 ITD/F691L and FLT3 ITD/D835Y. In KG-1a cells, HM43239 potently inhibited phosphorylation of SYK, STAT3 and STAT5. Moreover, it inhibited the proliferation and induced the apoptosis of leukemic stem cell (LSC) marker-expressing KG-1a cells (CD34+/CD38- cells), suggesting the possibility of targeting LSC. Furthermore, HM43239 showed to be exhibited good inhibitory activity against FLT3 mutated AML cell lines and effectively regress the tumors in MOLM-14 cells expressing FLT3 ITD/F691L or FLT3 ITD/D835Y xenograft mice models. On the other hand, it was confirmed that HM43239 strongly inhibited the phosphorylation of SYK in the medium of co-culture of stromal cells and AML cells. As a result, HM43239 alone more effectively induced tumor regression and prolonged the survival duration of animals than an approved FLT3 inhibitor (e.g. gilteritinib) in resistant FLT3 ITD/D835Y or ITD/F691L mutated MOLM-14 xenograft mice models. These results suggest that HM43239 could overcome the resistance induced by bone marrow microenvironment in AML patients. Taken together, HM43239 showed strong anticancer activity through various in vitro and in vivo preclinical models of AML, implicating the mechanism of overcoming resistance and preventing relapse. The effect of HM43239 in human would be demonstrated in ongoing Phase I/II clinical trials (NCT03850574) to develop promising therapeutics for patients with AML.

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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

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 exon 14 ins FLT3 D835Y	acute myeloid leukemia	predicted - sensitive	Tuspetinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Tuspetinib (HM43239) treatment resulted in tumor regression in a cell line xenograft model of acute myeloid leukemia expressing a FLT3 ITD mutation and FLT3 D835Y (Cancer Res 2021;81(13_Suppl):Abstract nr 1257).	detail...
FLT3 exon 14 ins FLT3 F691L	acute myeloid leukemia	predicted - sensitive	Tuspetinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Tuspetinib (HM43239) treatment resulted in tumor regression in a cell line xenograft model of acute myeloid leukemia expressing a FLT3 ITD mutation and FLT3 F691L (Cancer Res 2021;81(13_Suppl):Abstract nr 1257).	detail...