n-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide and Polycythemia-Vera

The classical BCR-ABL1-negative myeloproliferative neoplasms (MPN) include primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET). They are characterized by stem cell-derived clonal proliferation, harbor Janus kinase 2 (JAK2), or calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) driver mutations and exert an over activated JAK-signal transducer and activator of transcription (STAT) pathway. Therefore JAK inhibiting strategies have been successfully investigated in MPN clinical trials. Areas covered: The present review aims to provide a concise overview of the current and future role of JAK inhibitors in the therapeutic armamentarium of MPN. Expert opinion: The JAK1/JAK2 inhibitor ruxolitinib has clearly enriched the therapeutic armamentarium of MPN and is now licenced for more than five years in MF and over three years as second line in PV. Momelotinib, although of limited activity in MPN trials, demonstrated unique property of improving MF associated anemia. Less myelosuppressive or more selective JAK inhibitors like pacritinib, NS-01872 or Itacitinib are new promising agents tested in MF. JAK inhibition has become a cornerstone of MPN therapy and future efforts focus on ruxolitinib-based combinations and new JAK inhibitors.

Topics: Benzamides; Bridged-Ring Compounds; Clinical Trials as Topic; Fusion Proteins, bcr-abl; Humans; Janus Kinase Inhibitors; Myeloproliferative Disorders; Nitriles; Polycythemia Vera; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Thrombocythemia, Essential

Individualized medicine is important for patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, which are heterogeneous in terms of genetic mutation profile, prognosis, disease burden, and symptoms. Status of MPN driver mutations in JAK2, CALR, and MPL (or lack of one of these mutations) and other myeloid mutations (ASXL1, SRSF2, CBL, and IDH1/2, among others) affects diagnosis and prognosis. Management begins with estimating the prognosis, disease burden including MPN symptoms, and prevention of vascular events. Allogeneic stem cell transplantation is the definitive therapy in a subset of patients with myelofibrosis, the majority of whom receive JAK inhibition with ruxolitinib to relieve splenomegaly and symptoms and to prolong survival. Ruxolitinib is now a second-line therapy in polycythemia vera, with pegylated interferon being evaluated as a potential front-line therapy compared with hydroxyurea. The therapeutic landscape is evolving to include new JAK inhibitors, which may affect cytopenias (pacritinib and momelotinib), combination therapies including ruxolitinib, and novel targets such as pentraxin and telomerase. Assessing the therapeutic efficacy (including symptom impact) and toxicity of these new approaches is necessary to determine longitudinal management of MPNs in clinical practice and is a key component of "individualizing" care for patients with MPNs.

Topics: Adenylate Kinase; Benzamides; Bridged-Ring Compounds; Humans; Janus Kinase 2; Myeloproliferative Disorders; Polycythemia Vera; Precision Medicine; Primary Myelofibrosis; Pyrimidines; Stem Cell Transplantation; Thrombocythemia, Essential; Transplantation, Homologous

The discovery of JAK2V617F and other JAK-STAT-activating mutations in BCR-ABL1-negative myeloproliferative neoplasms (MPN) has led to the development of small-molecule ATP-mimetics that inhibit wild-type and mutant JAK. Here, we review the current experience with JAK inhibitors used for the treatment of myelofibrosis and polycythemia vera/essential thrombocythemia.. Consistent with the clonal complexity of MPN, JAK inhibitors have not thus far shown disease-modifying activity; treatment with these agents has however shown clinically meaningful benefits, particularly decreased splenomegaly and improvement in constitutional symptoms, in myelofibrosis patients. Although these benefits accrue with both JAK-2 (TG101348) and JAK-1/2 (INCB018424, CYT387) inhibitors, the mode of action (predominant anticlonal versus anticytokine activity) may be different between the two groups. It is possible that an optimal balance between JAK-1-inhibitory and JAK-2-inhibitory activities may broaden the therapeutic activity (i.e. anemia improvement), as has been preliminarily seen (CYT387).. Although JAK inhibitors have important benefits in myelofibrosis therapy, their role in polycythemia vera/essential thrombocythemia treatment is still being defined. The optimal dosing strategy and feasibility for combination with other therapeutic agents remains to be established. Another challenge is the identification of robust primary end-points that will support labeling claims for JAK inhibitors for the aforementioned indications.

Topics: Benzamides; Humans; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Nitriles; Polycythemia Vera; Primary Myelofibrosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrrolidines; Sulfonamides; Thrombocythemia, Essential

Somatic mutations in Janus kinase 2 (JAK2), including JAK2V617F, result in dysregulated JAK-signal transducer and activator transcription (STAT) signaling, which is implicated in myeloproliferative neoplasm (MPN) pathogenesis. CYT387 is an ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases (IC(50)=11 and 18 nM, respectively), with significantly less activity against other kinases, including JAK3 (IC(50)=155 nM). CYT387 inhibits growth of Ba/F3-JAK2V617F and human erythroleukemia (HEL) cells (IC(50) approximately 1500 nM) or Ba/F3-MPLW515L cells (IC(50)=200 nM), but has considerably less activity against BCR-ABL harboring K562 cells (IC=58 000 nM). Cell lines harboring mutated JAK2 alleles (CHRF-288-11 or Ba/F3-TEL-JAK2) were inhibited more potently than the corresponding pair harboring mutated JAK3 alleles (CMK or Ba/F3-TEL-JAK3), and STAT-5 phosphorylation was inhibited in HEL cells with an IC(50)=400 nM. Furthermore, CYT387 selectively suppressed the in vitro growth of erythroid colonies harboring JAK2V617F from polycythemia vera (PV) patients, an effect that was attenuated by exogenous erythropoietin. Overall, our data indicate that the JAK1/JAK2 selective inhibitor CYT387 has potential for efficacious treatment of MPN harboring mutated JAK2 and MPL alleles.

Topics: Alleles; Animals; Cell Line, Tumor; Cells, Cultured; Colony-Forming Units Assay; Drug Evaluation, Preclinical; Erythropoietin; Humans; Inhibitory Concentration 50; Janus Kinase 1; Janus Kinase 2; Leukemia, Erythroblastic, Acute; Mice; Mutation; Oncogene Proteins, Fusion; Polycythemia Vera; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Receptors, Thrombopoietin; STAT Transcription Factors; Substrate Specificity