Editorial
Copyright ©2010 Baishideng Publishing Group Co.
World J Clin Oncol. Feb 10, 2011; 2(2): 80-93
Published online Feb 10, 2011. doi: 10.5306/wjco.v2.i2.80
Table 1 Single-targeted and multi-targeted inhibitors of cellular tyrosine kinases ABL, SRC and janus kinase family
InhibitorTyrosine kinase targetNeoplasm(s) targetedClinical status
Bcr-Abl inhibitors
Imatinib mesylate (STI571)Bcr-Abl, Kit, PDGFRβCML, ALL, GISTsApproved
Nilotinib (AMN107)BcrAbl, Kit, PDGFRβCML, Pcp ALL, HS, SMApproved
Tyrphostin AG1024Bcr-Abl, P-AktCML (refract to STI571)Preclinical
ON012380Bcr-AblCMLPhase I
Tyrphostin AG957Bcr-AblCMLPreclinical
AdaphostinBcr-AblCMLPreclinical
NS-187Bcr-Abl, LynCML, Pcp ALLPreclinical
SRC family inhibitors
Dasatinib (BMS354825)Bcr-Abl, SRCAdult CML, Pcp ALLApproved
SKI-606Bcr-Abl, SRCPcp leukemia, breastPhase I/II
AZD0530Bcr-Abl, SRCSolid tumorsPhase I
Lung, liver, colorectalPhase II
TG100435SRC, Lyn, abl, yes, lck, EphB4Anti-cancerPreclinical
PD166326Bcr-Abl, SRC, lynCMLPreclinical
PD180970Bcr-Abl, SRC, KitCMLPreclinical
AZM475271SRCPancreaticPreclinical
CGP76030Bcr-Abl, SRCCML, prost, bone metPreclinical
PP1FYN, Lck, Kit, Bcr-AblCMLPreclinical
PP2SRC, Lck, Fyn, HckColonPreclinical
AP-23236SRCBone metastasesPreclinical
PD173955 + 56BA, Kit, csk, PDGFRβ, EGFRCMLPreclinical
SU6656Scr, Fyn, Yes, LynLymphomaPreclinical
CGP77675SRCBonePreclinical
SU11333 + 36SRCBreast, colonPreclinical
JAK inhibitors
CP-690 550JAK3ImmunogenicPreclinical
AG-490JAK2/3, EGFRLeukemia, gliomaPreclinical
WHI-P154JAK3, Hck, SykNeural precursor cellsPreclinical
WHI-P131JAK3Leukemia, GVHDPreclinical
WP-1034JAK, StatAMLPreclinical
LFM-A13JAK2, BTKLeukemiaPreclinical
Table 2 Tyrosine kinase inhibitors of the epidermal growth factor receptor tyrosine kinase family
InhibitorTyrosine kinase targetNeoplasm(s) targetedClinical status
Gefitinib (Iressa, ZD1839)EGFRLung, breastApproved
Erlotinib (Tarceva, OSI774)EGFRLungApproved
Lapatinib (Tykerb, GW-572016)ErbB1, ErbB2Breast, RCC, gastric, HN, NSCLCApproved
Canertinib (CI-1033)EGFR, ErbB2, ErbB3, ErbB4Breast, NSCLC, HNPhase I/II
NVP-AEE788EGFR, ErbB2, VEGFRSolid tumorsPhase II
XL647EGFR, ErbB2, VEGFR, EphB4CancerPhase I
PKI-166EGFR, ErbB2Adv solid tumorsPhase I
SU-11464ErbB2CancerPreclinical
EKB-569EGFR, ErbB2NSCLC, colorectal, solidPhase II
AG1478EGFRNasopharyngealPreclinical
CP724,714ErbB2Breast, adv solid tumorsPhase I/II
PD-158780EGFR, ErbB2, ErbB4CancerPreclinical
CP-654577ErbB2BreastPreclinical
BIBW2992EGFR, ErbB2NSCLC, HN, breastPhase II
HKI-272ErbB2Breast, solid tumorsPhase I/II
CL-387,785EGFR, ErbB2CancerPreclinical
CP358,774EGFRHN, ovarian, breastPhase II
MP 412EGFR, ErbB2NSCLC, breast, HN, pancreatic, prostatePhase I
Table 3 Tyrosine kinase inhibitors of the platelet derived growth factor receptor tyrosine kinase family
InhibitorTyrosine kinase targetNeoplasm(s) targetedClinical status
Leflunomide (SU101)PDGFRβ, EGFR, FGFRProstate cancerPhase II/III
Lestaurtinib (CEP-701)Flt3, Trk, VEGFR2Leukemia, pancreatic, AMLPhase II
Tandutinib (MLN518)Flt3, PDGFRβ, KitAMLPhase I/II
SU14813VEGFR2, PDGFRβ, Flt3Adv malignanciesPhase I, suspended
XL999FGFR, VEGFR1/2/3, PDGFRβ, Flt3CancerPhase II, suspended
VX-322Flt3, KitAMLPreclinical
SU5614Flt3AML, solid tumorsPreclinical, suspended
GTP-14564Flt3AMLPreclinical
KI23819Flt3AMLPreclinical
Gö6976Flt3, JAK2AMLPreclinical
AG1296PDGFRβ, Kit, Flt3AMLPreclinical
PKC412Kit, PDGFRβ, PKC, Flt3, VEGFR2Solid tumorsPhase II
OSI 817Kit, VEGFRSolid tumorsPreclinical
CP-868596PDGFRβAdv solid tumorsPhase I
NSCLCPhase II
Table 4 Tyrosine kinase inhibitors of the vascular endothelial growth factor receptor tyrosine kinase families
InhibitorTyrosine kinase targetNeoplasm(s) targetedClinical status
Sunitinib (Sutent,VEGFR1/2/3, PDGFRα/β, Kit,GIST (imatinib resist)Approved
SU11248)Flt3, CSF1R, RETAdv RCCApproved
NSCLCPhase III
Vandetanib (ZD6474)VEGFR2, EGFR, RETSolid tumorsPhase I/II
Adv NSCLCApproved
Medullary thyroidPhase II
Vatalanib (PTK787/ZK222584)VEGFR1/2/3, PDGFRβ, KitColorectal, prostate, RCC, MDS, AML, MMPhase III
Phase I/II
Sorafenib (BAY 43-9006)B-Raf, VEGFR2/3, PDGFRβ,Adv RCCApproved
Flt3, Kit, RAF, RETNSCLCPhase III
Melanoma, prostateDiff phases
Semaxinib (SU5416)VEGFR2, Kit, Flt3, Stat5, AKTAMLPhase II
Cediranib (AZD2171)VEGFR1/2/3, PDGFRβ, KitSolid tumorsPhase I/II/III
CEP-7055VEGFR1/2/3, Flt3Solid tumorsPhase  I/II
Dovitinib lactateVEGFR1/2, FGFR1/3, PDGFRβ,Multiple myelomaPhase II/III
(TKI258; CHIR258)Flt3, Kit, CSFR1
CP-547,632VEGFR2, FGFROvarian, lungPhase I/II
Pazopanib (GW786034)VEGFR1/2/3, PDGFRα/β, KitRCC,Approved;
Multiple myeloma;Phase I/II
solid tumorsPhase I/II
OSI-930VEGFR, KitCancer, anti-angiogenicPhase I/II
Foretinib (XL-880; GSK 1363089)VEGFR, c-METHCC, gastricPhase I/II
KRN-951VEGFR1/2/3, PDGFRβ, KitAdv cancerPhase I/II
SU10944VEGFRSolid tumorsPreclinical
ZK-CDKVEGFR1/2/3, PDGFRβ, CdksBreast, prostatePhase I/II, suspended
Axitinib (AG-13736)VEGFR1/2, PDGFRβ, KitSolid tumorsPhase II/III
Motesanib diphosphateVEGFR1/2, PDGFRβ, Kit, RETAnti-angiogenicPhase II
(AMG706)GIST (Imatinib resist)Phase II
NSCLCPhase III
Brivanib (BMS-582664)VEGFR2, FGFRSolid tumorsPhase I/II
PD173074VEGFR, FGFRSolid tumors, anti-angioPreclinical
Linifanib (M10-963; ABT-869PDGFRβ, VEGFR2, CSF1RNSCLC, HCC, RCCPhase II/III
BAY57-9352VEGFR2/3, PDGFRβ, KitAnti-angiogenicPhase I
SU11657TELPDGFRβ, VEGFR, Kit, Flt3CMMLPreclinical
Regorafenib (BAY 73-4506)VEGFR-2, Tie-2RCC; HCCPhase II
XL-184VEGFR-2, c-MET, c-Kit, Tie-2NSCLC, Glioblastoma, lymphomaPhase II
BIBF1120VEGFR2, PDGFR, FGFROvarianPhase II
Adv solid tumorsPhase I
AZD6244MEKNSCLC, pancreas melanomaPhase II
TSU-68 (SU6668)VEGFR2, PDGFRβ, FGFR, KitAdv solid tumorsPhase I/II/III
Table 5 Resistance mechanism to tyrosine kinase inhibitors
MechanismTarget/drug/diseaseRef.
1(Secondary) mutation of the tyrosine kinaseBcr-Abl in CML, FLT3 in AML, EGFR in NSCLC, c-KIT in GIST[12]
2Gene amplification and subsequent overexpression of the protein kinaseBcr-Abl in CML + c-KIT in GIST[12]
3aActivation of other signaling pathwaysPDGFR mutation in c-KIT mutated GIST, MET overexpression in EGFR mutated NSCLC[50]
3bOverexpression of kinases downstream of the kinaseLYN in CML
4Lower intracellular drug concentrations because of:
4aExtracellular sequestration of the inhibitor by binding to α acid glycoproteinPKC412, imatinib[99]
4bDecreased expression or activity of drug influx pumpsOCT1, imatinib[52]
4cIncreased expression or activity of drug efflux pumpsBCRP, P-glycoprotein (imatinib)[51,60]