Editorial
Copyright
©2010 Baishideng Publishing Group Co. , Limited. All rights reserved.
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
Inhibitor Tyrosine kinase target Neoplasm(s) targeted Clinical status Bcr-Abl inhibitors Imatinib mesylate (STI571) Bcr-Abl, Kit, PDGFRβ CML, ALL, GISTs Approved Nilotinib (AMN107) BcrAbl, Kit, PDGFRβ CML, Pcp ALL, HS, SM Approved Tyrphostin AG1024 Bcr-Abl, P-Akt CML (refract to STI571) Preclinical ON012380 Bcr-Abl CML Phase I Tyrphostin AG957 Bcr-Abl CML Preclinical Adaphostin Bcr-Abl CML Preclinical NS-187 Bcr-Abl, Lyn CML, Pcp ALL Preclinical SRC family inhibitors Dasatinib (BMS354825) Bcr-Abl, SRC Adult CML, Pcp ALL Approved SKI-606 Bcr-Abl, SRC Pcp leukemia, breast Phase I/II AZD0530 Bcr-Abl, SRC Solid tumors Phase I Lung, liver, colorectal Phase II TG100435 SRC, Lyn, abl, yes, lck, EphB4 Anti-cancer Preclinical PD166326 Bcr-Abl, SRC, lyn CML Preclinical PD180970 Bcr-Abl, SRC, Kit CML Preclinical AZM475271 SRC Pancreatic Preclinical CGP76030 Bcr-Abl, SRC CML, prost, bone met Preclinical PP1 FYN, Lck, Kit, Bcr-Abl CML Preclinical PP2 SRC, Lck, Fyn, Hck Colon Preclinical AP-23236 SRC Bone metastases Preclinical PD173955 + 56 BA, Kit, csk, PDGFRβ, EGFR CML Preclinical SU6656 Scr, Fyn, Yes, Lyn Lymphoma Preclinical CGP77675 SRC Bone Preclinical SU11333 + 36 SRC Breast, colon Preclinical JAK inhibitors CP-690 550 JAK3 Immunogenic Preclinical AG-490 JAK2/3, EGFR Leukemia, glioma Preclinical WHI-P154 JAK3, Hck, Syk Neural precursor cells Preclinical WHI-P131 JAK3 Leukemia, GVHD Preclinical WP-1034 JAK, Stat AML Preclinical LFM-A13 JAK2, BTK Leukemia Preclinical
Table 2 Tyrosine kinase inhibitors of the epidermal growth factor receptor tyrosine kinase family
Inhibitor Tyrosine kinase target Neoplasm(s) targeted Clinical status Gefitinib (Iressa, ZD1839) EGFR Lung, breast Approved Erlotinib (Tarceva, OSI774) EGFR Lung Approved Lapatinib (Tykerb, GW-572016) ErbB1, ErbB2 Breast, RCC, gastric, HN, NSCLC Approved Canertinib (CI-1033) EGFR, ErbB2, ErbB3, ErbB4 Breast, NSCLC, HN Phase I/II NVP-AEE788 EGFR, ErbB2, VEGFR Solid tumors Phase II XL647 EGFR, ErbB2, VEGFR, EphB4 Cancer Phase I PKI-166 EGFR, ErbB2 Adv solid tumors Phase I SU-11464 ErbB2 Cancer Preclinical EKB-569 EGFR, ErbB2 NSCLC, colorectal, solid Phase II AG1478 EGFR Nasopharyngeal Preclinical CP724,714 ErbB2 Breast, adv solid tumors Phase I/II PD-158780 EGFR, ErbB2, ErbB4 Cancer Preclinical CP-654577 ErbB2 Breast Preclinical BIBW2992 EGFR, ErbB2 NSCLC, HN, breast Phase II HKI-272 ErbB2 Breast, solid tumors Phase I/II CL-387,785 EGFR, ErbB2 Cancer Preclinical CP358,774 EGFR HN, ovarian, breast Phase II MP 412 EGFR, ErbB2 NSCLC, breast, HN, pancreatic, prostate Phase I
Table 3 Tyrosine kinase inhibitors of the platelet derived growth factor receptor tyrosine kinase family
Inhibitor Tyrosine kinase target Neoplasm(s) targeted Clinical status Leflunomide (SU101) PDGFRβ, EGFR, FGFR Prostate cancer Phase II/III Lestaurtinib (CEP-701) Flt3, Trk, VEGFR2 Leukemia, pancreatic, AML Phase II Tandutinib (MLN518) Flt3, PDGFRβ, Kit AML Phase I/II SU14813 VEGFR2, PDGFRβ, Flt3 Adv malignancies Phase I, suspended XL999 FGFR, VEGFR1/2/3, PDGFRβ, Flt3 Cancer Phase II, suspended VX-322 Flt3, Kit AML Preclinical SU5614 Flt3 AML, solid tumors Preclinical, suspended GTP-14564 Flt3 AML Preclinical KI23819 Flt3 AML Preclinical Gö6976 Flt3, JAK2 AML Preclinical AG1296 PDGFRβ, Kit, Flt3 AML Preclinical PKC412 Kit, PDGFRβ, PKC, Flt3, VEGFR2 Solid tumors Phase II OSI 817 Kit, VEGFR Solid tumors Preclinical CP-868596 PDGFRβ Adv solid tumors Phase I NSCLC Phase II
Table 4 Tyrosine kinase inhibitors of the vascular endothelial growth factor receptor tyrosine kinase families
Inhibitor Tyrosine kinase target Neoplasm(s) targeted Clinical status Sunitinib (Sutent, VEGFR1/2/3, PDGFRα/β, Kit, GIST (imatinib resist) Approved SU11248) Flt3, CSF1R, RET Adv RCC Approved NSCLC Phase III Vandetanib (ZD6474) VEGFR2, EGFR, RET Solid tumors Phase I/II Adv NSCLC Approved Medullary thyroid Phase II Vatalanib (PTK787/ZK222584) VEGFR1/2/3, PDGFRβ, Kit Colorectal, prostate, RCC, MDS, AML, MM Phase III Phase I/II Sorafenib (BAY 43-9006) B-Raf, VEGFR2/3, PDGFRβ, Adv RCC Approved Flt3, Kit, RAF, RET NSCLC Phase III Melanoma, prostate Diff phases Semaxinib (SU5416) VEGFR2, Kit, Flt3, Stat5, AKT AML Phase II Cediranib (AZD2171) VEGFR1/2/3, PDGFRβ, Kit Solid tumors Phase I/II/III CEP-7055 VEGFR1/2/3, Flt3 Solid tumors Phase I/II Dovitinib lactate VEGFR1/2, FGFR1/3, PDGFRβ, Multiple myeloma Phase II/III (TKI258; CHIR258) Flt3, Kit, CSFR1 CP-547,632 VEGFR2, FGFR Ovarian, lung Phase I/II Pazopanib (GW786034) VEGFR1/2/3, PDGFRα/β, Kit RCC, Approved; Multiple myeloma; Phase I/II solid tumors Phase I/II OSI-930 VEGFR, Kit Cancer, anti-angiogenic Phase I/II Foretinib (XL-880; GSK 1363089) VEGFR, c-MET HCC, gastric Phase I/II KRN-951 VEGFR1/2/3, PDGFRβ, Kit Adv cancer Phase I/II SU10944 VEGFR Solid tumors Preclinical ZK-CDK VEGFR1/2/3, PDGFRβ, Cdks Breast, prostate Phase I/II, suspended Axitinib (AG-13736) VEGFR1/2, PDGFRβ, Kit Solid tumors Phase II/III Motesanib diphosphate VEGFR1/2, PDGFRβ, Kit, RET Anti-angiogenic Phase II (AMG706) GIST (Imatinib resist) Phase II NSCLC Phase III Brivanib (BMS-582664) VEGFR2, FGFR Solid tumors Phase I/II PD173074 VEGFR, FGFR Solid tumors, anti-angio Preclinical Linifanib (M10-963; ABT-869 PDGFRβ, VEGFR2, CSF1R NSCLC, HCC, RCC Phase II/III BAY57-9352 VEGFR2/3, PDGFRβ, Kit Anti-angiogenic Phase I SU11657 TELPDGFRβ, VEGFR, Kit, Flt3 CMML Preclinical Regorafenib (BAY 73-4506) VEGFR-2, Tie-2 RCC; HCC Phase II XL-184 VEGFR-2, c-MET, c-Kit, Tie-2 NSCLC, Glioblastoma, lymphoma Phase II BIBF1120 VEGFR2, PDGFR, FGFR Ovarian Phase II Adv solid tumors Phase I AZD6244 MEK NSCLC, pancreas melanoma Phase II TSU-68 (SU6668) VEGFR2, PDGFRβ, FGFR, Kit Adv solid tumors Phase I/II/III
Table 5 Resistance mechanism to tyrosine kinase inhibitors
Mechanism Target/drug/disease Ref. 1 (Secondary) mutation of the tyrosine kinase Bcr-Abl in CML, FLT3 in AML, EGFR in NSCLC, c-KIT in GIST [12 ] 2 Gene amplification and subsequent overexpression of the protein kinase Bcr-Abl in CML + c-KIT in GIST [12 ] 3a Activation of other signaling pathways PDGFR mutation in c-KIT mutated GIST, MET overexpression in EGFR mutated NSCLC [50 ] 3b Overexpression of kinases downstream of the kinase LYN in CML 4 Lower intracellular drug concentrations because of: 4a Extracellular sequestration of the inhibitor by binding to α acid glycoprotein PKC412, imatinib [99 ] 4b Decreased expression or activity of drug influx pumps OCT1, imatinib [52 ] 4c Increased expression or activity of drug efflux pumps BCRP, P-glycoprotein (imatinib) [51 ,60 ]