fedratinib and lestaurtinib

Discovery of the JAK2 V617F mutation in the myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) has stimulated great interest in the underlying molecular mechanisms and treatment of these diseases. Along with acceleration of technologies, novel mutations in genes such as MPL, LNK, and CBL have been discovered that converge on the JAK-STAT pathway. Several additional novel mutations in genes involved in epigenetic regulation of the genome, including TET2, ASXL1, DNMT3A, and IDH1/2, have emerged, in addition to several mutations in cellular splicing machinery. While understanding of the pathogenetic mechanisms of these novel mutations in MPNs has improved, it is still lagging behind the pace of mutation discovery. Concurrent with molecular discoveries, especially with regard to JAK-STAT signaling, therapeutic development has accelerated in recent years. More than ten JAK kinase inhibitors have been advanced into clinical trials. Recently the first JAK2 inhibitor was approved for use in patients with PMF. Most JAK-targeting agents share similar characteristics with regard to clinical benefit, consisting of improvements in splenomegaly, constitutional symptoms, and cytopenias, for example. It remains to be determined if JAK2 inhibitors can considerably impact disease progression and bone marrow histologic features (e.g., fibrosis) or significantly impact the JAK2 allele burden. While JAK2 inhibitors appear to be promising in PV and ET, they need to be compared with standard therapies, such as hydroxyurea or interferon-based therapies. Future clinical development will focus on optimal combination partners and agents that target alternative mechanisms, deepen the response, and achieve molecular remissions.

Topics: Adaptor Proteins, Signal Transducing; Alleles; Benzamides; Bridged-Ring Compounds; Carbazoles; Chromatin; Dioxygenases; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Furans; Gene Expression Regulation; Humans; Ikaros Transcription Factor; Intracellular Signaling Peptides and Proteins; Isocitrate Dehydrogenase; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Nitriles; Polycomb Repressive Complex 2; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-cbl; Pyrazoles; Pyrimidines; Pyrrolidines; Receptors, Thrombopoietin; Repressor Proteins; Signal Transduction; Spliceosomes; Sulfonamides

The discovery of an activating tyrosine kinase mutation JAK2V617F in myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) has resulted in the development of JAK2 inhibitors, of which several are being evaluated in phase I/II clinical studies. It is important to recognize that because the V617F mutation is localized in a region outside the adenosine triphosphate (ATP)-binding pocket of JAK2 enzyme, ATP-competitive inhibitors of JAK2 kinase (like the current JAK2 inhibitors in the clinic) are not likely to discriminate between wild-type and mutant JAK2 enzymes. Therefore, JAK2 inhibitors, by virtue of their near equipotent activity against wild-type JAK2 that is important for normal hematopoiesis, may have adverse myelosuppression as an expected side effect, if administered at doses that aim to completely inhibit the mutant JAK2 enzyme. While they may prove to be effective in controlling hyperproliferation of hematopoietic cells in PV and ET, they may not be able to eliminate mutant clones. On the other hand, JAK inhibitors may have great therapeutic benefit by controlling the disease for patients with MPNs who suffer from debilitating signs (eg, splenomegaly) or constitutional symptoms (which presumably result from high levels of circulating cytokines that signal through JAK enzymes). Indeed, the primary clinical benefits observed so far in MF patients have been significant reduction is splenomegaly, elimination of debilitating disease-related symptoms, and weight gain. Most importantly, patients with and without the JAK2V617F mutation appear to benefit to the same extent. In this review we summarize current clinical experience with JAK2 inhibitors in MPNs.

Topics: Animals; Carbazoles; Clinical Trials as Topic; Drug Delivery Systems; Drug Evaluation, Preclinical; Furans; Humans; Janus Kinase 2; Mice; Mutation, Missense; Myeloproliferative Disorders; Nitriles; Point Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrrolidines; Signal Transduction; Splenomegaly; Sulfonamides; Weight Gain

The BCR-ABL-negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Historically, complex biochemical alterations defining these heterogeneously distinct malignancies have remained elusive and constrained available therapy options. The discovery of Janus kinase (JAK) mutations collectively present in BCR-ABL-negative MPNs has led to a resurgence of medical interest in JAK-STAT targeted treatment modalities, as well as provided a unique platform for inhibiting symptom-directing proinflammatory cytokines. INCB018424, CYT387, SB1518, and TG101348 are among the most propitious JAK2 inhibitors under investigation, providing substantial improvement in constitutional symptoms, transfusion-dependent cytopenias, and reduction in spleen size. Despite their attributes, evidence of complete or partial remission has yet to be observed with therapy. Many uncertainties surrounding the full clinical potential of JAK2 inhibitors persist. Treatment guidelines addressing optimal stages for drug implementation, ideal dosing parameters and criteria for medication continuation/withdrawal may effectively resolve these ongoing concerns and provide advancements in the morbidity and mortality of these multifaceted disease processes.

Topics: Animals; Benzamides; Bridged-Ring Compounds; Carbazoles; Furans; Humans; Janus Kinase 2; Myeloproliferative Disorders; Nitriles; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrrolidines; Sulfonamides