piperidines and ponatinib

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

The old-fashioned anticancer approaches, aiming at arresting cancer cell proliferation interfering with non-specific targets (e.g. DNA), have been replaced, in the last decades, by more specific target oriented ones. Nonetheless, single-target approaches have not always led to optimal outcomes because, for its complexity, cancer needs to be tackled at various levels by modulation of several targets. Although at present, combinations of individual singletarget drugs represent the most clinically practiced therapeutic approaches, the modulation of multiple proteins by a single drug, in accordance with the polypharmacological strategy, has become more and more appealing. In the perspective of a multi-target approach, the closely related evolutionary members of the tyrosine kinase family are ideal candidates. Indeed, tyrosine kinase activities are not only critical in tumor phenotype maintenance, but also modulate several functions in the tumor microenvironment. Consequently, several multikinase inhibitors were approved in the last decade, and many new molecules are currently in preclinical or clinical development. In the present review we report on the most widely FDA-approved multitargeted drugs, discussing about their mechanism of action and outlining the clinical trials that have brought them to approval.

Topics: Anilides; Crizotinib; Humans; Imatinib Mesylate; Imidazoles; Indoles; Neoplasms; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridazines; Pyridines; Pyrroles; Quinazolines; Receptor Protein-Tyrosine Kinases; Sorafenib; Sunitinib

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

Regulating blood cholesterol (Chol) levels by pharmacotherapy has successfully improved cardiovascular health. There is growing interest in the role of Chol precursors in the treatment of diseases. One sterol precursor, desmosterol (Des), is a potential pharmacological target for inflammatory and neurodegenerative disorders. However, elevating levels of the precursor 7-dehydrocholesterol (7-DHC) by inhibiting the enzyme 7-dehydrocholesterol reductase is linked to teratogenic outcomes. Thus, altering the sterol profile may either increase risk toward an adverse outcome or confer therapeutic benefit depending on the metabolite affected by the pharmacophore. In order to characterize any unknown activity of drugs on Chol biosynthesis, a chemical library of Food and Drug Administration-approved drugs was screened for the potential to modulate 7-DHC or Des levels in a neural cell line. Over 20% of the collection was shown to impact Chol biosynthesis, including 75 compounds that alter 7-DHC levels and 49 that modulate Des levels. Evidence is provided that three tyrosine kinase inhibitors, imatinib, ponatinib, and masitinib, elevate Des levels as well as other substrates of 24-dehydrocholesterol reductase, the enzyme responsible for converting Des to Chol. Additionally, the mechanism of action for ponatinib and masitinib was explored, demonstrating that protein levels are decreased as a result of treatment with these drugs.

Topics: Benzamides; Cell Line, Tumor; Dehydrocholesterols; Desmosterol; Drug Evaluation, Preclinical; Gene Expression Regulation; High-Throughput Screening Assays; Humans; Imidazoles; Nerve Tissue Proteins; Oxidoreductases Acting on CH-CH Group Donors; Piperidines; Prescription Drugs; Pyridazines; Pyridines; Thiazoles; United States; United States Food and Drug Administration