title: What is next beyond janus kinase 2 inhibitors for primary myelofibrosis?
abstract: OBJECTIVE
  Although the approval of the janus kinase (JAK) inhibitor ruxolitinib for therapy of patients with myelofibrosis represents an important step in the development of targeted therapy for these patients, JAK inhibitors do not eradicate the disease, and a review of novel agents with mechanisms of action complementary to JAK2 enzymatic inhibition is timely.
  
  
  RESULTS
  There are several compounds with different mechanisms of action undergoing preclinical and clinical testing in myelofibrosis. Heat shock protein inhibitors and histone deacetylase inhibitors induce JAK2 degradation and downregulation of intracellular oncogenic signalling, and may overcome resistance to JAK2 inhibitors. Reversal of bone marrow fibrosis is still a therapeutic challenge in this disease, and mAbs targeting transforming growth factor-β and lysyl oxidase like-2 may prove efficacious. Promising compounds inhibiting signal transducer and activator of transcription 5 activity and inducing megakaryocyte polyploidization are in preclinical testing.
  
  
  CONCLUSIONS
  Although none of these new drugs have been approved for therapy of myelofibrosis, their activity is being tested in clinical trials, alone or in combination with JAK2 inhibitors. Patients with myelofibrosis should be encouraged to participate in clinical trials testing novel compounds for this disorder, particularly if they have failed a trial of JAK2 inhibitors.
authors: Hematology and Oncology Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
authors: Fabio P S
authors: FP
authors: Santos
authors: Srdan
authors: S
authors: Verstovsek
mesh_terms: D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D055728:Primary Myelofibrosis / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*
chemical_list: D047428:Protein Kinase Inhibitors; D053614:Janus Kinase 2