title: Off-Target Effects of BCR-ABL and JAK2 Inhibitors.
abstract: The advent of targeted oncolytic agents has created a revolution in the treatment of malignancies. Perhaps best exemplified in myeloproliferative neoplasms (MPN), the tyrosine kinase inhibitors, including inhibitors of BCR-ABL tyrosine kinase and JAK2, have dramatically changed outcomes in persons with MPN. However, clinically relevant dosing of these adenosine triphosphate-mimetic agents in humans leads to inhibition of numerous tyrosine kinases beyond those touted by drug manufacturers and studied in landmark clinical trials. These so-called off-target effects have been linked to both clinical efficacy and toxicity. Rational drug development and serendipitous discovery of drug molecules allows the clinician to select targeted oncolytic agents to treat a specific clinical diagnosis and/or avoid exacerbation of concomitant disease states due to effects upon signaling pathways. Understanding the off-target binding and effects upon signaling pathway of the agents approved for the treatment of MPN will empower the clinician to adroitly select pharmacotherapy, predict toxicities, and utilize these agents in clinical practice for indications beyond MPN.
authors.affiliation: *Division of Hematology/Oncology, University of Arizona Cancer Center †Department of Pharmacy Services, University of Arizona Medical Center, Tucson, AZ ‡Department of Clinical Pharmacy, West Virginia University School of Pharmacy §Department of Pharmacy, West Virginia University Hospitals, Morgantown, WV ∥Department of Pharmacy Practice-Oncology Acute Care, Duquesne University Mylan School of Pharmacy, Pittsburgh, PA.
authors.forename: Myke R
authors.initials: MR
authors.lastname: Green
authors.forename: Michael D
authors.initials: MD
authors.lastname: Newton
authors.forename: Karen M
authors.initials: KM
authors.lastname: Fancher
mesh_terms: D000814:Aniline Compounds / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002227:Carbazoles / Q000627:therapeutic use; D000069439:Dasatinib / Q000627:therapeutic use; D064420:Drug-Related Side Effects and Adverse Reactions; D004802:Eosinophilia / Q000188:drug therapy; D005663:Furans; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy; D006086:Graft vs Host Disease / Q000188:drug therapy; D006248:Harringtonines / Q000627:therapeutic use; D000077863:Homoharringtonine; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D007093:Imidazoles / Q000627:therapeutic use; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D008415:Mastocytosis / Q000188:drug therapy; D009196:Myeloproliferative Disorders / Q000188:drug therapy*; D009570:Nitriles / Q000627:therapeutic use; D011087:Polycythemia Vera / Q000188:drug therapy; D055728:Primary Myelofibrosis / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000188:drug therapy; D011720:Pyrazoles / Q000627:therapeutic use; D011724:Pyridazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D012595:Scleroderma, Systemic / Q000188:drug therapy; D012899:Smallpox / Q000188:drug therapy; D013920:Thrombocythemia, Essential / Q000188:drug therapy; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D002227:Carbazoles; D005663:Furans; D006248:Harringtonines; D007093:Imidazoles; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D011743:Pyrimidines; D011804:Quinolines; C545373:ponatinib; C471992:bosutinib; D000077863:Homoharringtonine; C540383:ruxolitinib; D000068877:Imatinib Mesylate; C119379:lestaurtinib; D016044:Fusion Proteins, bcr-abl; D053614:Janus Kinase 2; C498826:nilotinib; C506918:bafetinib; D000069439:Dasatinib