Mechanism of Multikinase Inhibitor Action

Tumour development involves the dysregulation of normal cell processes such as cell growth and proliferation, as well as angiogenesis (the formation of new blood vessels).1 A range of receptor kinases are involved in these processes, including vascular endothelial growth factor receptor (VEGFR), Platelet-derived growth factor receptor (PDGFR), stem cell factor (c-kit), FLT3, fibroblast growth factor Receptor (FGFR), which can be hyperactivated during tumour formation and progression.1

Tumour growth may be prevented by inhibiting the action of these hyperactivated receptor kinases, and as tumour progression usually involves the action of multiple kinases rather than just one, it is logical to target multiple kinases.1 This can be achieved through the use of a number of singly targeted agents, or through a single inhibitor that targets multiple kinases.

Major kinase pathways inhibited by regorafenib, sorafenib, vandetanib, sunitinib, and imatinib are shown in the table below:

Inhibition of protein kinases by multikinase inhibitors (IC50 values[nM])a

Oncogenic markers Regorafenib2,3b Sorafenib4b Vandetanib5c Sunitini6b Imatinib7b
BRAF-WT 28 22 - - -
BRAF V600E 19 38 - - -
C-KIT 7 68 - - 100
VEGFR-1 13 - 1,600 2 -
VEGFR-2 4.2 90 40 9 -
VEGFR-3 46 20 108 17 -
PDGFR-β 22 57 - 8 100
FLT3 162 58 - - >1000
FGFR 201 580 - - -

aBased on a limited number of publications; bbiochemical assays against a panel of kinases; csystem not clearly identified in source reference.


1Lacouture ME, et al. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. The Oncologist. 2008;13:1001-1011.
2Wilhelm SM, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129;245–255.
3US Food and Drug Administration (FDA) Clinical Pharmacology and Biopharmaceutics Review(S) NDA 203-085 available at (accessed 22 August 2014)
4European Medicines Agency. Nexavar® (sorafenib) Summary of Product Characteristics 2014.
5Morabito A, et al. Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. The Oncologist. 2009;14:378–390.
6European Medicines Agency. Sutent® (sunitinib) Summary of Product Characteristics 2014
7Deininger M, Buchdunger E, Duker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005;105: 2640-2653.

Last update: 22 August 2014