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Ref Type Journal Article
PMID (38641704)
Authors Yang T, Ke H, Liu J, An X, Xue J, Ning J, Hao F, Xiong L, Chen C, Wang Y, Zheng J, Gao B, Bao Z, Gong K, Zhang L, Zhang F, Guo S, Li QX
Title Narazaciclib, a novel multi-kinase inhibitor with potent activity against CSF1R, FLT3 and CDK6, shows strong anti-AML activity in defined preclinical models.
Journal Vol Issue Date Pages Journal Short Title
Scientific reports 14 1 2024 Apr 19 9032 Sci Rep
URL
Abstract Text CSF1R is a receptor tyrosine kinase responsible for the growth/survival/polarization of macrophages and overexpressed in some AML patients. We hypothesized that a novel multi-kinase inhibitor (TKi), narazaciclib (HX301/ON123300), with high potency against CSF1R (IC50 ~ 0.285 nM), would have anti-AML effects. We tested this by confirming HX301's high potency against CSF1R (IC50 ~ 0.285 nM), as well as other kinases, e.g. FLT3 (IC50 of ~ 19.77 nM) and CDK6 (0.53 nM). An in vitro proliferation assay showed that narazaciclib has a high growth inhibitory effect in cell cultures where CSF1R or mutant FLT3-ITD variants that may be proliferation drivers, including primary macrophages (IC50 of 72.5 nM) and a subset of AML lines (IC50 < 1.5 μM). In vivo pharmacology modeling of narazaciclib using five AML xenografts resulted in: inhibition of MV4-11 (FLT3-ITD) subcutaneous tumor growth and complete suppression of AM7577-PDX (FLT3-ITD/CSF1Rmed) systemic growth, likely due to the suppression of FLT3-ITD activity; complete suppression of AM8096-PDX (CSF1Rhi/wild-type FLT3) growth, likely due to the inhibition of CSF1R ("a putative driver"); and nonresponse of both AM5512-PDX and AM7407-PDX (wild-type FLT3/CSF1Rlo). Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.

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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 hematologic cancer sensitive Narazaciclib Preclinical - Cell culture Actionable In a preclinical study, Narazaciclib (ON123300) inhibited proliferation of cells expressing FLT3-ITD and FLT3 D835Y in culture (PMID: 38641704). 38641704
FLT3 exon 14 ins FLT3 Y842H hematologic cancer sensitive Narazaciclib Preclinical - Cell culture Actionable In a preclinical study, Narazaciclib (ON123300) inhibited proliferation of cells expressing FLT3-ITD and FLT3 Y842H in culture (PMID: 38641704). 38641704
FLT3 exon 14 ins FLT3 F691L hematologic cancer sensitive Narazaciclib Preclinical - Cell culture Actionable In a preclinical study, Narazaciclib (ON123300) inhibited proliferation of cells expressing FLT3-ITD and FLT3 F691L in culture (PMID: 38641704). 38641704
FLT3 exon 14 ins acute myeloid leukemia sensitive Narazaciclib Preclinical - Pdx & cell culture Actionable In a preclinical study, Narazaciclib (ON123300) inhibited proliferation of acute myeloid leukemia cell lines harboring FLT3-ITD in culture, and decreased tumor burden in a cell line xenograft model and a patient-derived xenograft (PDX) model (PMID: 38641704). 38641704
FLT3 exon 14 ins FLT3 N701K hematologic cancer sensitive Narazaciclib Preclinical - Cell culture Actionable In a preclinical study, Narazaciclib (ON123300) inhibited proliferation of cells expressing FLT3-ITD and FLT3 N701K in culture (PMID: 38641704). 38641704
FLT3 exon 14 ins acute myeloid leukemia sensitive Azacitidine + Narazaciclib Preclinical - Cell line xenograft Actionable In a preclinical study, addition of Vidaza (azacitidine) enhanced the anti-tumor activity of Narazaciclib (ON123300) in a cell line xenograft model of acute myeloid leukemia harboring FLT3-ITD (PMID: 38641704). 38641704
FLT3 exon 14 ins hematologic cancer sensitive Narazaciclib Preclinical - Cell culture Actionable In a preclinical study, Narazaciclib (ON123300) inhibited proliferation of cells expressing FLT3-ITD in culture (PMID: 38641704). 38641704
FLT3 exon 14 ins FLT3 D835V hematologic cancer sensitive Narazaciclib Preclinical - Cell culture Actionable In a preclinical study, Narazaciclib (ON123300) inhibited proliferation of cells expressing FLT3-ITD and FLT3 D835V in culture (PMID: 38641704). 38641704
FLT3 F691L hematologic cancer sensitive Narazaciclib Preclinical - Cell culture Actionable In a preclinical study, Narazaciclib (ON123300) inhibited proliferation of cells expressing FLT3 F691L in culture (PMID: 38641704). 38641704
FLT3 exon 14 ins FLT3 D835F hematologic cancer sensitive Narazaciclib Preclinical - Cell culture Actionable In a preclinical study, Narazaciclib (ON123300) proliferation of cells expressing FLT3-ITD and FLT3 D835F in culture (PMID: 38641704). 38641704