piperidines and midostaurin

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in approximately one third of patients with acute myeloid leukemia (AML), either by internal tandem duplications (FLT3-ITD), or by a point mutation mainly involving the tyrosine kinase domain (FLT3-TKD). Patients with FLT3-ITD have a high risk of relapse and low cure rates. Several FLT3 tyrosine kinase inhibitors have been developed in the last few years with variable kinase inhibitory properties, pharmacokinetics, and toxicity profiles. FLT3 inhibitors are divided into first generation multi-kinase inhibitors (such as sorafenib, lestaurtinib, midostaurin) and next generation inhibitors (such as quizartinib, crenolanib, gilteritinib) based on their potency and specificity of FLT3 inhibition. These diverse FLT3 inhibitors have been evaluated in myriad clinical trials as monotherapy or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front-line, relapsed or refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. In this practical question-and-answer-based review, the main issues faced by the leukemia specialists on the use of FLT3 inhibitors in AML are addressed.

Topics: Aniline Compounds; Antineoplastic Agents; Benzimidazoles; Benzothiazoles; Carbazoles; DNA Methylation; Enzyme Inhibitors; fms-Like Tyrosine Kinase 3; Furans; Humans; Leukemia, Myeloid, Acute; Mutation; Neoplasm Recurrence, Local; Phenylurea Compounds; Piperidines; Prognosis; Pyrazines; Randomized Controlled Trials as Topic; Sorafenib; Staurosporine; Treatment Outcome

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene arise in 25-30% of all acute myeloid leukemia (AML) patients. These mutations lead to constitutive activation of the protein product and are divided in two broad types: internal tandem duplication (ITD) of the juxtamembrane domain (25% of cases) and point mutations in the tyrosine kinase domain (TKD). Patients with FLT3 ITD mutations have a high relapse risk and inferior cure rates, whereas the role of FLT3 TKD mutations still remains to be clarified. Additionally, growing research indicates that FLT3 status evolves through a disease continuum (clonal evolution), where AML cases can acquire FLT3 mutations at relapse - not present in the moment of diagnosis. Several FLT3 inhibitors have been tested in patients with FLT3-mutated AML. These drugs exhibit different kinase inhibitory profiles, pharmacokinetics and adverse events. First-generation multi-kinase inhibitors (sorafenib, midostaurin, lestaurtinib) are characterized by a broad-spectrum of drug targets, whereas second-generation inhibitors (quizartinib, crenolanib, gilteritinib) show more potent and specific FLT3 inhibition, and are thereby accompanied by less toxic effects. Notwithstanding, all FLT3 inhibitors face primary and acquired mechanisms of resistance, and therefore the combinations with other drugs (standard chemotherapy, hypomethylating agents, checkpoint inhibitors) and its application in different clinical settings (upfront therapy, maintenance, relapsed or refractory disease) are under study in a myriad of clinical trials. This review focuses on the role of FLT3 mutations in AML, pharmacological features of FLT3 inhibitors, known mechanisms of drug resistance and accumulated evidence for the use of FLT3 inhibitors in different clinical settings.

Topics: Aniline Compounds; Antineoplastic Agents; Benzimidazoles; Benzothiazoles; Carbazoles; Drug Resistance, Multiple; Drug Resistance, Neoplasm; fms-Like Tyrosine Kinase 3; Forecasting; Furans; Hematopoietic Stem Cell Transplantation; Humans; Imidazoles; Leukemia, Myeloid, Acute; Maintenance Chemotherapy; Mutation; Phenylurea Compounds; Piperidines; Point Mutation; Protein Kinase Inhibitors; Pyrazines; Pyridazines; Recurrence; Sorafenib; Staurosporine

Outcomes for the majority of patients with acute myeloid leukemia (AML) remain poor. Over the past decade, significant progress has been made in the understanding of the cytogenetic and molecular determinants of AML pathogenesis. One such advance is the identification of recurring mutations in the FMS-like tyrosine kinase 3 gene (FLT3). Currently, this marker, which appears in approximately one-third of all AML patients, not only signifies a poorer prognosis but also identifies an important target for therapy. FLT3 inhibitors have now undergone clinical evaluation in Phase I, II and III clinical trials, as both single agents and in combination with chemotherapeutics. Unfortunately, to date, none of the FLT3 inhibitors have gained FDA approval for the treatment of patients with AML. Yet, several promising FLT3 inhibitors are being evaluated in all phases of drug development.. This review aims to highlight the agents furthest along in their development. It also focuses on those FLT3 inhibitors that are being evaluated in combination with other anti-leukemia agents.. The authors believe that the field of research for FLT3 inhibitors remains promising, despite the historically poor prognosis of this subgroup of patients with AML. The most promising areas of research will likely be the elucidation of the mechanisms of resistance to FLT3 inhibitors, and development of potent FLT3 inhibitors alone or in combination with hypomethylating agents, cytotoxic chemotherapy or with other targeted agents.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Benzothiazoles; Drug Resistance, Neoplasm; fms-Like Tyrosine Kinase 3; Humans; Imidazoles; Leukemia, Myeloid, Acute; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridazines; Sorafenib; Staurosporine

Approximately 90 % of gastrointestinal tumors (GISTs) harbor an activating mutation in KIT or PDGFR alpha oncogene known to confer imatinib sensitivity. Imatinib is a tyrosine kinase inhibitor of KIT and PDGFRs that yields a 6-months progression-free survival (PFS) rate of 80 % in patients with advanced GISTs. Several studies have shown that response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFR alpha. Moreover, most if not all patients treated with imatinib for advanced GIST will secondarily develop progressive disease under treatment. In the majority of cases, such progressions are the result of acquired resistance due to occurrence of secondary C-KIT mutations; especially for GIST with primary exon 11 mutations. Sunitinib is another approved drug and an inhibitor of multiple tyrosine kinases including KIT, PDGFR alpha as well as PDGFR beta and VEGFRs which are associated with angiogenesis. Sunitinib, in phase II and III trials was associated with durable clinical benefit in nearly 25 % of patients with advanced GIST resistant/intolerant to imatinib. Clearly, a better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors may allow in the near future new individualized therapeutic strategies for GISTs patients.

Topics: Antineoplastic Agents; Benzamides; Benzenesulfonates; Disease Progression; Drug Resistance, Neoplasm; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Indoles; Mutation; Neoplasm Proteins; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperazines; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyridines; Pyrimidines; Pyrroles; Receptor, Platelet-Derived Growth Factor alpha; Sorafenib; Staurosporine; Sunitinib; Thiazoles

Recently, several targeted agents have been developed for specific subsets of patients with acute myeloid leukaemia (AML), including midostaurin, the first FDA-approved FLT3 inhibitor for newly diagnosed patients with FLT3 mutations. However, in the initial Phase I/II clinical trials, some patients without FLT3 mutations had transient responses to midostaurin, suggesting that this multi-targeted kinase inhibitor might benefit AML patients more broadly. Here, we demonstrate submicromolar efficacy of midostaurin in vitro and efficacy in vivo against wild-type (wt) FLT3-expressing AML cell lines and primary cells, and we compare its effectiveness with that of other FLT3 inhibitors currently in clinical trials. Midostaurin was found to synergize with standard chemotherapeutic drugs and some targeted agents against AML cells without mutations in FLT3. The mechanism may involve, in part, the unique kinase profile of midostaurin that includes proteins implicated in AML transformation, such as SYK or KIT, or inhibition of ERK pathway or proviability signalling. Our findings support further investigation of midostaurin as a chemosensitizing agent in AML patients without FLT3 mutations.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Benzimidazoles; Benzothiazoles; Cell Line, Tumor; Cell Proliferation; Drug Synergism; fms-Like Tyrosine Kinase 3; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Mice; Mutation; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazines; Sorafenib; Staurosporine; Syk Kinase

Mutations in two type-3 receptor tyrosine kinases (RTKs), KIT and FLT3, are common in both acute myeloid leukaemia (AML) and systemic mastocytosis (SM) and lead to hyperactivation of key signalling pathways. A large number of tyrosine kinase inhibitors (TKIs) have been developed that target either FLT3 or KIT and significant clinical benefit has been demonstrated in multiple clinical trials. Given the structural similarity of FLT3 and KIT, it is not surprising that some of these TKIs inhibit both of these receptors. This is typified by midostaurin, which has been approved by the US Food and Drug Administration for mutant FLT3-positive AML and for KIT D816V-positive SM. Here, we compare the in vitro activities of the clinically available FLT3 and KIT inhibitors with those of midostaurin against a panel of cells expressing a variety of oncogenic FLT3 or KIT receptors, including wild-type (wt) FLT3, FLT3-internal tandem duplication (ITD), FLT3 D835Y, the resistance mutant FLT3-ITD+ F691L, KIT D816V, and KIT N822K. We also examined the effects of these inhibitors in vitro and in vivo on cells expressing mutations in c-CBL found in AML that result in hypersensitization of RTKs, such as FLT3 and KIT. The results show a wide spectrum of activity of these various mutations to these clinically available TKIs.

Topics: Aniline Compounds; Antineoplastic Agents; Benzimidazoles; Benzothiazoles; Cell Line, Tumor; Drug Screening Assays, Antitumor; fms-Like Tyrosine Kinase 3; Hematologic Neoplasms; Humans; Mutant Proteins; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-cbl; Proto-Oncogene Proteins c-kit; Pyrazines; Pyrazoles; Pyrroles; Sorafenib; Staurosporine; Triazines

Topics: Benzamides; Benzimidazoles; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C8 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Indoles; Inhibitory Concentration 50; Microsomes, Liver; Phthalazines; Piperidines; Pyridines; Pyridones; Pyrimidinones; Quinolones; Staurosporine; Thiazoles

CD30 is a novel therapeutic target in human mast cell (MC) neoplasms. In this 'comparative oncology' study, we examined CD30 expression and regulation in neoplastic canine MC using a panel of immunomodulatory cytokines [interleukin-2 (IL-2), IL-4, IL-5, IL-6, IL-13 and stem cell factor (SCF)] and the canine mastocytoma cell lines NI-1 and C2. Of all cytokines tested IL-4 was found to downregulate expression of CD30 in NI-1 and C2 cells. We also found that the CD30-targeting antibody-conjugate brentuximab vedotin induces growth inhibition and apoptosis in both MC lines. Next, we asked whether IL-4-induced downregulation of CD30 interferes with brentuximab vedotin-effects. Indeed, pre-incubation of NI-1 cells with IL-4 decreased responsiveness towards brentuximab vedotin. To overcome IL-4-mediated resistance, we applied drug combinations and found that brentuximab vedotin synergizes with the Kit-targeting drugs masitinib and PKC412 in inhibiting growth of NI-1 and C2 cells. In summary, CD30 is a new marker and IL-4-regulated target in neoplastic canine MC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Brentuximab Vedotin; Cell Line, Tumor; Cytokines; Dog Diseases; Dogs; Down-Regulation; Drug Synergism; Female; Immunoconjugates; Interleukin-4; Ki-1 Antigen; Male; Mastocytosis; Piperidines; Pyridines; Staurosporine; Thiazoles

Topics: Antineoplastic Agents; Azacitidine; Biomedical Research; Carbazoles; Carboplatin; Cytarabine; Daunorubicin; Decitabine; Enzyme Inhibitors; Etoposide; Flavonoids; Furans; Humans; Leukemia, Myeloid, Acute; Mitoxantrone; Piperidines; Quinolones; Staurosporine; Topotecan; Tretinoin

We have established preclinical models for the development of drug resistance to vincristine (a major drug used in the treatment of pediatric rhabdomyosarcoma) using cell lines. The RD cell line has a mutant P53 phenotype and does not have detectable P-glycoprotein (P-gp) or multidrug resistance-related protein (MRP) despite expressing low levels of mdr-1 mRNA, which encodes P-gp and mrp1 mRNA. Resistant variants of RD were derived by exposure to increasing concentrations of vincristine. This was repeated on six occasions, resulting in three cell lines which could tolerate 64 x the IC(50) concentration. Six independent agents were tested for their ability to prevent the development of resistance in this model. Despite at least 10 attempts, resistance did not develop in the presence of the multidrug resistance (MDR) modulators PSC833, VX710, and XR9576. This strongly suggests that these agents may delay or even prevent the development of resistance to vincristine. This was also confirmed in a second rhabdomyosarcoma cell line, Rh30. In contrast, the agents indomethacin (MRP1 modulator), CGP41251 (protein kinase C inhibitor), and dexrazoxane (putative MDR prevention agent) did not affect the development of resistance in the RD model. Characterization of the resistant cell lines indicated the presence of increased mdr-1 and P-gp expression, which resulted in resistance to the agents doxorubicin, etoposide, and vincristine but not cisplatin. The resistance could be modulated using PSC833 or VX710, confirming that functional P-gp is present. No apparent differences were seen between the resistant cell lines derived in the absence and presence of the various agents. These experiments strongly suggest that the development of MDR may be preventable using modulators of MDR and merit clinical studies to test this hypothesis.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Child; Cisplatin; Cyclosporins; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Etoposide; Gene Expression Regulation, Neoplastic; Humans; Indomethacin; Inhibitory Concentration 50; Piperidines; Pyridines; Quinolines; Razoxane; Rhabdomyosarcoma; RNA, Neoplasm; Staurosporine; Time Factors; Tumor Cells, Cultured; Vincristine