pazopanib and Hematologic-Diseases

Topics: Activin Receptors, Type II; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; beta-Thalassemia; Graft vs Host Disease; Hematologic Diseases; Humans; Immunoglobulin Fc Fragments; Indazoles; Interleukin-1 Receptor-Associated Kinases; Internet; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Lymphoma, B-Cell; Multiple Myeloma; Protein Kinase Inhibitors; Pyrimidines; Recombinant Fusion Proteins; Sulfonamides; Telangiectasia, Hereditary Hemorrhagic

Myelosuppression has been observed with several multikinase angiogenesis inhibitors in clinical studies, although the frequency and severity varies among the different agents. Inhibitors targeting vascular endothelial growth factor receptor (VEGFR) often inhibit other kinases, which may contribute to their adverse-event profiles.. Kinase selectivity of pazopanib, sorafenib, and sunitinib was evaluated in a panel of 242 kinases. Cellular potency was measured using autophosphorylation assays. Effect on human bone marrow progenitor growth in the presence of multiple growth factors was evaluated and correlated with the kinase selectivity.. Sunitinib inhibited more kinases than pazopanib and sorafenib, at potencies within 10-fold of VEGFR-2. All three compounds potently inhibited VEGFR-2, platelet-derived growth factor receptor-beta and c-Kit, However, pazopanib was less active against Flt-3 in both kinase and cellular assays. The inhibitory properties of pazopanib, sorafenib, and sunitinib were dependent on the growth factor used to initiate bone marrow colony formation. Addition of stem cell factor and/or Flt-3 ligand with granulocyte-macrophage colony stimulating factor resulted in significant shifts in potency for sorafenib and sunitinib but less so for pazopanib.. Activity against c-kit and Flt-3 by multikinase angiogenesis inhibitors provide a potential explanation for the differences in myelosuppression observed with these agents in patients.

Topics: Angiogenesis Inhibitors; Benzenesulfonates; Cell Line, Tumor; fms-Like Tyrosine Kinase 3; Hematologic Diseases; Hematopoietic Stem Cells; Humans; Indazoles; Indoles; Inhibitory Concentration 50; Myelopoiesis; Niacinamide; Phenylurea Compounds; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyridines; Pyrimidines; Pyrroles; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Substrate Specificity; Sulfonamides; Sunitinib