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Ref Type Journal Article
PMID (32247263)
Authors Wang Y, Zhang L, Tang X, Luo J, Tu Z, Jiang K, Ren X, Xu F, Chan S, Li Y, Zhang Z, Ding K
Title GZD824 as a FLT3, FGFR1 and PDGFRα Inhibitor Against Leukemia In Vitro and In Vivo.
Journal Vol Issue Date Pages Journal Short Title
Translational oncology 13 4 2020 Apr 01 100766 Transl Oncol
URL
Abstract Text GZD824 is a novel third-generation BCR-ABL inhibitor. It entered Phase II clinical trials in China and Phase Ib clinical trials in USA in 2019 for treatment of patients with resistant chronic myeloid leukemia (CML). We found that at concentrations below 10 nM, GZD824 significantly suppresses FLT3, FGFR1 and PDGFRα kinase activities and inhibits their signal pathways in MV4-11Flt3-ITD, KG-1FGFR1OP2-FGFR1 and EOL-1FIP1L1-PDGFRa leukemia cells. It selectively inhibits the growth of MV4-11Flt3-ITD, KG-1FGFR1OP2-FGFR1 and EOL-1FIP1L1-PDGFRa cells, and also effectively suppresses the growth of Ba/F3-FLT3-ITD cells harboring F691I and other mutations with IC50 values <10 nM. GZD824 induces G0/G1 phase arrest and apoptosis in MV4-11, KG-1 and EOL-1 cells and activates cleavage of caspase-3 and PARP. In MV4-11, Ba/F3-ITD-F691I and KG-1 mouse xenograft models, GZD824 at 10 or 20 mg/kg, q2d, p.o. almost completely eradicates tumors. It also inhibits the viability of primary leukemic blasts from a FLT3-ITD positive AML patient but not those expressing native FLT3. Thus GZD824 suppresses leukemia cells of FLT3-ITD-driven AML and other hematologic malignancies driven by FGFR1 or PDGFRa, and it may be considered to be a novel agent for the treatment of leukemia.

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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
Olverembatinib Olverembatinib 26 2
Drug Name Trade Name Synonyms Drug Classes Drug Description
Olverembatinib HQP 1351|HQP-1351|GZD824 dimesylate|GZD824|HQP1351 ABL1 Inhibitor 8 FGFR1 Inhibitor 28 FLT3 Inhibitor 69 KIT Inhibitor 57 PDGFR-alpha Inhibitor 9 Olverembatinib (HQP1351) is a third-generation BCR-ABL inhibitor and multikinase inhibitor that inhibits KIT, ABL1, FGFR1, FLT3, and PDGFRA (PMID: 32247263), which potentially induces apoptosis, and inhibits tumor cell growth, migration, and invasion (PMID: 31673329).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FLT3 E654D missense unknown FLT3 E654D lies within the protein kinase domain of the Flt3 protein (UniProt.org). E654D has been identified in the scientific literature (PMID: 32247263), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Dec 2023).
FLT3 Y842R missense unknown FLT3 Y842R lies within the protein kinase domain of the Flt3 protein (UniProt.org). Y842R has been identified in the scientific literature (PMID: 32247263), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Dec 2023).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins FLT3 E654D acute myeloid leukemia predicted - sensitive Olverembatinib Preclinical - Patient cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) reduced Flt3 and Stat5 activation and inhibited growth of patient-derived acute myeloid leukemia cells harboring FLT3-ITD and FLT3 E654D in culture (PMID: 32247263). 32247263
FLT3 exon 14 ins FLT3 D835I hematologic cancer predicted - sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 D835I demonstrated decreased proliferation in response to Olverembatinib (HQP1351) in culture, but were less sensitive to treatment than cells co-expressing FLT3-ITD with other FLT3 kinase domain mutations (PMID: 32247263). 32247263
FLT3 R834Q hematologic cancer predicted - sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3 R834Q demonstrated decreased proliferation in response to Olverembatinib (HQP1351) in culture, but were less sensitive to treatment than cells expressing other FLT3 kinase domain mutations (PMID: 32247263). 32247263
FLT3 exon 14 ins FLT3 D835V hematologic cancer predicted - sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 D835V demonstrated decreased proliferation in response to Olverembatinib (HQP1351) in culture, but were less sensitive to treatment than cells co-expressing FLT3-ITD with other FLT3 kinase domain mutations (PMID: 32247263). 32247263
FLT3 exon 14 ins FLT3 D835N hematologic cancer sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) inhibited growth of transformed cells expressing FLT3-ITD and FLT3 D835N in culture (PMID: 32247263). 32247263
FLT3 exon 14 ins FLT3 N676D hematologic cancer sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) inhibited growth of transformed cells expressing FLT3-ITD and FLT3 N676D in culture (PMID: 32247263). 32247263
FLT3 exon 14 ins FLT3 Y842R hematologic cancer sensitive Olverembatinib Preclinical Actionable In a preclinical study, Olverembatinib (HQP1351) inhibited growth of transformed cells expressing FLT3-ITD and FLT3 Y842R in culture (PMID: 32247263). 32247263
FLT3 exon 14 ins FLT3 D835G hematologic cancer sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) inhibited growth of transformed cells expressing FLT3-ITD and FLT3 D835G in culture (PMID: 32247263). 32247263
FLT3 exon 14 ins FLT3 Y842H hematologic cancer sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) inhibited growth of transformed cells expressing FLT3-ITD and FLT3 Y842H in culture (PMID: 32247263). 32247263
FLT3 exon 14 ins FLT3 D835A hematologic cancer sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) inhibited growth of transformed cells expressing FLT3-ITD and FLT3 D835A in culture (PMID: 32247263). 32247263
FLT3 D835Y hematologic cancer sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) inhibited growth of transformed cells expressing FLT3 D835Y in culture (PMID: 32247263). 32247263
FLT3 exon 14 ins acute myeloid leukemia sensitive Olverembatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Olverembatinib (HQP1351) reduced Flt3 and Stat5 phosphorylation, induced cell cycle arrest and apoptosis, and inhibited growth of acute myeloid leukemia cells harboring FLT3-ITD in culture, and suppressed tumor growth, decreased Flt3 activation, and induced apoptosis in cell line xenograft models (PMID: 32247263). 32247263
FLT3 exon 14 ins FLT3 D835Y hematologic cancer predicted - sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD and FLT3 D835Y demonstrated decreased proliferation in response to Olverembatinib (HQP1351) in culture, but were less sensitive to treatment than cells co-expressing FLT3-ITD with other FLT3 kinase domain mutations (PMID: 32247263). 32247263
FLT3 exon 14 ins FLT3 F691I hematologic cancer sensitive Olverembatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Olverembatinib (HQP1351) reduced Flt3 and Stat5 phosphorylation and inhibited growth of transformed cells expressing FLT3-ITD and FLT3 F691I in culture, and suppressed tumor growth, decreased Flt3 activation, and induced apoptosis in cell line xenograft models (PMID: 32247263). 32247263
FLT3 D835H hematologic cancer predicted - sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3 D835H demonstrated decreased proliferation in response to Olverembatinib (HQP1351) in culture, but were less sensitive to treatment than cells expressing other FLT3 kinase domain mutations (PMID: 32247263). 32247263
FLT3 exon 14 ins hematologic cancer sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) inhibited growth of transformed cells expressing FLT3-ITD in culture (PMID: 32247263). 32247263
FLT3 D835V hematologic cancer predicted - sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3 D835V demonstrated decreased proliferation in response to Olverembatinib (HQP1351) in culture, but were less sensitive to treatment than cells expressing other FLT3 kinase domain mutations (PMID: 32247263). 32247263
FLT3 exon 14 ins FLT3 G697R hematologic cancer sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) inhibited growth of transformed cells expressing FLT3-ITD and FLT3 G697R in culture (PMID: 32247263). 32247263