Tyrosine kinase inhibitors: Multi-targeted or single-targeted?

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

BTK: Bruton’s tyrosine kinase; CML: Chronic myeloid leukemia; Pcp: Philadelphia chromosome positive; ALL: Acute lymphoblastic leukemia; GIST: Gastrointestinal stromal tumors; HS: Hypereosinophilic syndrome; SM: Systemic mastocytosis; GVHD: Graft-versus-host disease; Cancer: Several cancer indications; PDGFR: Platelet derived growth factor receptor; EGFR: Epidermal growth factor receptor.

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

Trk: Nerve growth factor receptor tyrosine kinase; PKC: Protein kinase C; RCC: Renal cell carcinoma; HN: Head and neck cancer; NSCLC: Non small cell lung cancer; EGFR: Epidermal growth factor receptor.

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

Trk: Nerve growth factor receptor tyrosine kinase; PKC: Protein kinase C; RCC: Renal cell carcinoma; HN: Head and neck cancer; NSCLC: Non small cell lung cancer; PDGFR: Platelet derived growth factor receptor; EGFR: Epidermal growth factor receptor; AML: Acute myeloid leukaemia.

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

CMML: Chronic myelomonocytic leukemia; MDS: Myelodysplastic syndromes; MM: Multiple myeloma; HCC: Hepatocellular carcinoma; RCC: Renal cell carcinoma; NSCLC: Non small cell lung cancer; PDGFR: Platelet derived growth factor receptor; EGFR: Epidermal growth factor receptor; AML: Acute myeloid leukaemia.

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]

NSCLC: Non small cell lung cancer; PDGFR: Platelet derived growth factor receptor; EGFR: Epidermal growth factor receptor; CML: Chronic myeloid leukemia; GIST: Gastrointestinal stromal tumors; AML: Acute myeloid leukaemia.