cabozantinib and Leukemia--Myeloid--Acute

Mutations in the FMS-like tyrosine kinase 3 (

Topics: Animals; Drug Discovery; Drug Resistance, Neoplasm; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Models, Molecular; Mutation; Protein Kinase Inhibitors; Small Molecule Libraries

Topics: Anilides; Animals; Core Binding Factor Alpha 2 Subunit; Humans; Leukemia, Myeloid, Acute; Mice; Oncogene Proteins, Fusion; Proto-Oncogene Proteins c-kit; Pyridines; RUNX1 Translocation Partner 1 Protein; TOR Serine-Threonine Kinases

FMS-like tyrosine kinase 3 (FLT3) was an important therapeutic target in acute myeloid leukemia (AML). We synthesized two series of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives possessing the semicarbazide moiety and 2,2,2-trifluoro-N,N'-dimethylacetamide moiety as the linker. The cell proliferation assay in vitro against HL-60 and MV4-11 cell lines demonstrated that most series I compounds containing semicarbazide moiety had more potent than Cabozantinib. Furthermore, the enzyme assay showed that compound 12c and 12g were potent FLT3 inhibitors with IC

Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Cell Proliferation; Drug Design; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Protein Kinase Inhibitors; Semicarbazides; Structure-Activity Relationship; Tumor Cells, Cultured

Topics: Anilides; Apoptosis Regulatory Proteins; Biomarkers; Cell Line, Tumor; Cell Survival; Cytarabine; DNA Mutational Analysis; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; fms-Like Tyrosine Kinase 3; Gene Deletion; Humans; Leukemia, Myeloid, Acute; Metabolic Networks and Pathways; Mutation; Pyridines; Tandem Repeat Sequences; Tumor Suppressor Protein p53

The clinical management of pediatric acute myeloid leukemia (AML) is still challenging and identification of drugs that can enhance the efficacy of standard of care is a potential therapeutic strategy. We show that pamidronate, a FDA-approved drug used for bone disorders, is an attractive candidate for AML treatment. Pamidronate inhibits proliferation and induces apoptosis of AML cells regardless of cellular and genetic heterogeneity. Pamidronate displays selective anti-AML activity by preferentially inhibiting survival and colony formation of AML CD34

Topics: Anilides; Annexin A5; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzothiazoles; Bone Density Conservation Agents; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Child; Cytarabine; Daunorubicin; Drug Repositioning; Humans; Leukemia, Myeloid, Acute; Neoplastic Stem Cells; Pamidronate; Phenylurea Compounds; Primary Cell Culture; Protein Prenylation; Protein Processing, Post-Translational; Pyridines; ras Proteins

Cabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways.. Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy. Cabozantinib was administered in 28-day cycles, and dose escalation occurred via cohorts. A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess FLT3-inhibitory activity in FLT3-mutant cell lines.. Among 18 patients enrolled, 5 were found to harbor FLT3/ITD mutations. Sixteen patients (89%) had relapsed/refractory AML, and most were treated with 2 or more lines of prior treatment. No dose-limiting toxicities (DLTs) were detected at the first dose level (40 mg daily), but 2 patients experienced DLTs at the next level (60 mg daily). The remaining patients were then dosed at 40 mg daily, the maximum tolerated dose (MTD). Additional grade 2 or higher toxicities, possibly/probably related to cabozantinib, included fatigue, nausea, transaminitis, and electrolyte imbalance. No patients had a marrow response according to formal criteria, but 4 had peripheral blast reductions; 2 of these 4 patients transiently cleared circulating blasts. One patient experienced a reduction in marrow blasts, and 1 had stable disease. The FLT3-inhibitory activity of plasma samples, as assessed with the PIA, revealed potent and sustained inhibition in FLT3/ITD and, notably, F691 tyrosine kinase domain (TKD)-mutant cells.. Cabozantinib is well tolerated in AML patients at an MTD of 40 mg daily and is a potent inhibitor of FLT3/ITD- and F691 TKD-altered tyrosine kinases. Cancer 2018;124:306-14. © 2017 American Cancer Society.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Drug Resistance, Neoplasm; Female; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Protein Kinase Inhibitors; Pyridines

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Drug Discovery; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Mice; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proteomics; Xenograft Model Antitumor Assays

Cabozantinib is an oral multikinase inhibitor that exhibits anti-tumor activity in several cancers. We found that cabozantinib was significantly cytotoxic to MV4-11 and Molm-13 cells that harbored FLT3-ITD, resulting in IC50 values of 2.4 nM and 2.0 nM, respectively. However, K562, OCI-AML3 and THP-1 (leukemia cell lines lacking FLT3-ITD) were resistant to cabozantinib, showing IC50 values in the micromolar range. Cabozantinib arrested MV4-11 cell growth at the G0/G1 phase within 24 h, which was associated with decreased phosphorylation of FLT3, STAT5, AKT and ERK. Additionally, cabozantinib induced MV4-11 cell apoptosis in a dose-dependent manner (as indicated by annexin V staining and high levels of cleaved caspase 3 and PARP-1), down-regulated the anti-apoptotic protein survivin and up-regulated the pro-apoptotic protein Bak. Thus, cabozantinib is selectively cytotoxic to leukemia cells with FLT3-ITD, causing cell-cycle arrest and apoptosis. In mouse xenograft model, cabozantinib significantly inhibited MV4-11 and Molm-13 tumor growth at a dosage of 10 mg/kg and showed longer survival rate. Clinical trials evaluating the efficacy of cabozantinib in acute myeloid leukemia (AML) with FLT3-ITD are warranted.

Topics: Anilides; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Cell Cycle Checkpoints; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; fms-Like Tyrosine Kinase 3; Gene Duplication; Genetic Predisposition to Disease; HL-60 Cells; Humans; K562 Cells; Leukemia, Myeloid, Acute; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Phenotype; Protein Kinase Inhibitors; Pyridines; Signal Transduction; Time Factors; Tumor Burden; U937 Cells; Xenograft Model Antitumor Assays