Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Cancer Research, GlaxoSmithKline, Collegeville, PA 19426, USA. rakesh.2.kumar@gsk.com
R
R
Kumar
M-C
MC
Crouthamel
D H
DH
Rominger
R R
RR
Gontarek
P J
PJ
Tummino
R A
RA
Levin
A G
AG
King
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006402:Hematologic Diseases / Q000139:chemically induced / Q000201:enzymology; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D038042:Myelopoiesis / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D000077157:Sorafenib; D013379:Substrate Specificity; D013449:Sulfonamides / Q000494:pharmacology*; D000077210:Sunitinib; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D001557:Benzenesulfonates; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D009536:Niacinamide; C516667:pazopanib; D000077157:Sorafenib; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D051941:fms-Like Tyrosine Kinase 3; D000077210:Sunitinib