316 K.-H. Thierauch & A. Chlistalla
method to assess the selectivity of inhibitors for endothelial cells is the study of their effect on cell proliferation. Only VEGF-stimulated endothelial cell proliferation but not tumor cell proliferation should be inhibited. As can be seen in Table 1 many of the angiogenesis kinase inhibitors, which target angiogenesis are not specific for endothelial cells but inhibit tumor cell growth directly. One would like to argue that the mechanism does not matter, since the effect on tumor growth is relevant. However, it has to be taken into consideration that the toxicity of such agents may be paralleling their lack of specificity. Standard tumor therapy generally includes combinations with cytotoxic chemotherapeutics. If a toxic kinase inhibitor is added to the cytotoxic regimen, the quality of life of patients is influenced and a reduction of the dose of chemotherapeutics may be required, thus jeopardizing the overall therapeutic effect.
The more than 500 kinases derived from the human genome have been ordered in a phylogenetic tree and families of kinases are defined.33 VEGFRs belong to the receptor tyrosine kinase family V with split kinase domain, which is closely related to the receptor tyrosine family III, which also has a split kinase domain but the number of extracellular Ig domains is reduced from seven to five. Fabian et al. elegantly showed the breadth of kinases inhibited by a group of inhibitors labeled with the tag “angiogenesis inhibitor”.34 Activity was tested against 113 different kinases. In Fig. 1, the inhibitory spectra are depicted of some of the clinically investigated anti-angiogenic kinase inhibitors taken from this publication, demonstrating the questionable selectivity of presently developed inhibitors, possibly with the exception of PTK787/ZK 222584 (PTK/ZK).
In the following, we discuss several kinase inhibitors in clinical development, that target VEGFR kinases. We will also present basic information of their preclinical properties.
5. Kinase Inhibitors in Clinical Development
The structures of the molecules in clinical development with available information are given in Fig. 2. Data regarding their kinase selectivity and cellular efficacy are summarized in Table 2.
Table 1. Overview of tyrosine kinase inhibitors with anti-angiogenic effects currently in clinical development.
|
|
|
|
|
ASCO 2005 |
Drug |
Phase of dev. |
Safe dose |
Side effects |
Current efficacy data |
Abstract # |
|
|
|
|
|
|
BAY 43-9006 |
Phase III |
400 mg bid |
Diarrhoea, skin rash, |
Second line RCC positive |
3005 |
(Sorafenib, Bayer) |
|
|
hand-foot syndrome, |
phase III trial. Phase III in |
3037 |
|
|
|
fatigue, hypertension |
advanced melanoma ongoing. |
3054 |
|
|
|
|
Phase II program ongoing in |
3062 |
|
|
|
|
various indications |
|
PTK787/ZK |
Phase III |
1250 mg QD |
Ataxia, vertigo, nausea, |
Various phase I/II studies have |
3 |
222584 (Vatalanib, |
|
|
hypertension, venous |
shown promising activity in |
5042 |
Novartis, Schering |
|
|
thromboembolism, |
RCC, GBM, CRC and |
|
AG) |
|
|
fatigue |
mesothelioma. Phase III trial |
|
|
|
|
|
in first line treatment of CRC |
|
|
|
|
|
(CONFIRM1) did not reach |
|
|
|
|
|
primary endpoint |
|
SU11248 |
Phase III |
50 mg QD |
Fatigue, lethargy, |
Ongoing phase III evaluation |
3006 |
(Sunitinib, Pfizer) |
|
|
nausea, stomatitis, diar- |
in first and second line RCC |
3040 |
|
|
|
rhea,myelosuppresion |
and Imatinib-resistant GIST |
|
|
|
|
|
and NSCLC |
|
(Continued)
Inhibitors Kinase
317
Table 1. (Continued ).
|
|
|
|
|
ASCO 2005 |
Drug |
Phase of dev. |
Safe dose |
Side effects |
Current efficacy data |
Abstract # |
|
|
|
|
|
|
ZD6474 |
Phase II |
< 300 mg |
Diarrhoea, hypertension, |
Promising data in phase I and |
3023 |
(Astra-Zeneca) |
|
QD |
hepatic toxicity, |
phase II especially in NSCLC |
7102 |
|
|
|
cutaneous rash, |
second line. Phase III in second |
|
|
|
|
asymptomatic QTc |
line NSCLC in combination |
|
|
|
|
prolongation |
with docetaxel planned to start |
|
|
|
|
|
in 2005. Phase II in SCLC |
|
|
|
|
|
ongoing |
|
AG-013736 |
Phase II |
5 mg bid |
Fatigue, nausea, |
(Pfizer) |
|
|
diarrhea, hoarseness, |
|
|
|
anorexia, weight loss, |
|
|
|
Grade 3/4 AEs include |
|
|
|
htn (12%), aggravated |
|
|
|
htn (6%), diarrhea (6%), |
|
|
|
fatigue (6%), blister (4%) |
|
|
|
and limb pain |
Promising data in phase II |
3003 |
second line RCC; phase II studies now planned in breast cancer, melanoma, NSCLC, thyroid cancer
AEE 788 |
Phase I |
< 550 mg |
Diarrhea, skin rash, |
Phase I trials in GBm and |
3028 |
(Novartis) |
|
QD |
fatigue, nausea, and |
other solid tumors ongoing |
3063 |
|
|
|
anorexia, thrush, and |
|
|
|
|
|
emesis |
|
|
|
|
|
|
|
|
Chlistalla .A & Thierauch .H-.K 318
Table 1. (Continued ).
|
|
|
|
|
ASCO 2005 |
Drug |
Phase of dev. |
Safe dose |
Side effects |
Current efficacy data |
Abstract # |
|
|
|
|
|
|
AMG 706 |
Phase II |
125 QD |
Hypertension, fatigue, |
Evidence of tumor regression |
3013 |
(Amgen) |
|
|
headache |
in early development. Ongoing |
|
|
|
|
|
phase II studies in |
|
|
|
|
|
imatinib-resistant GIST, |
|
|
|
|
|
NSCLC, breast cancer and |
|
|
|
|
|
CRC |
|
AZD 2171 |
Phase I |
45 mg QD |
Diarrhoea, nausea, |
Several phase I in solid tumors |
3002 |
(Astra-Zeneca) |
|
|
fatigue, elevated liver |
ongoing |
3030 |
|
|
|
markers,vomiting, |
|
3049 |
|
|
|
hypoglycemia, |
|
|
|
|
|
hypertension |
|
|
BIB1120 |
|
300 mg bid |
Nausea, vomiting, and |
Phase I trials in advanced solid |
3031 |
(Boehringer |
|
|
diarrhoea. Elevations of |
malignancies ongoing |
3054 |
Ingelheim) |
|
|
hepatic enzymes |
|
|
Chir-258 |
Phase I |
100 mg qd |
Nausea, vomiting, and |
Phase I trial in advanced solid |
3044 |
(Chiron) |
|
|
diarrhoea, fatgue, |
malignancies ongoing |
|
|
|
|
anemia, headache, |
|
|
|
|
|
pruritic rush, |
|
|
|
|
|
hypertension (DLT) |
|
|
(Continued)
319 Inhibitors Kinase
Table 1. (Continued ).
|
|
|
|
|
ASCO 2005 |
Drug |
Phase of dev. |
Safe dose |
Side effects |
Current efficacy data |
Abstract # |
|
|
|
|
|
|
GW-786034 |
Phase II |
800 mg qd |
Nausea, fatigue, |
Phase I/II in advanced solid |
3012 |
(GSK) |
|
or 300 mg |
hypertension, anorexia, |
tumors ongoing |
|
|
|
bid |
vomiting, hair |
|
|
|
|
|
depigmentation, |
|
|
SU5416 |
Dev. stopped |
125 mg/ m2 |
Headache, nausea, |
Modest signs of efficacy in |
|
(Semaxinib) |
after phase III |
i.v. twice |
vomiting, asthenia, |
several phase I/II trials in |
|
|
|
weekly |
phlebitis, dyspnea |
different cancer populations. |
|
|
|
|
|
Failed to show efficacy in two |
|
|
|
|
|
phase III trials in combination |
|
|
|
|
|
with either 5-FU/LV or |
|
|
|
|
|
Irinotecan/5-FU/LV in first line |
|
|
|
|
|
metastatic colorectal cancer. |
|
|
|
|
|
Compound withdrawn from |
|
|
|
|
|
further development |
|
Abstracts from the ASCO-Meeting 2005 are obtained from http://www.asco.org/ac/1,1003,_12-002634-00_18-0034,0.asp
Chlistalla .A & Thierauch .H-.K 320
|
|
F |
H |
H |
F |
N |
N |
F |
|
|
|
O |
O |
Cl |
|
H
N
N
O
Sorafenib Bay43-9006 / Bayer + Onyx
Cl |
O |
|
OH
NH HO
O
N
N
N
Vatalanib PTK787/ZK222584
Novartis /Schering
O N
N
H
N
F H
O
N
H
Sunitinib SU11248 / Pfizer
Kinase Inhibitors |
321 |
F
Br
HN
O
N
ON
N
ZD6474 / Astra-Zeneca
N
N
SN H
ON H
AG-13736 / Pfizer
N
|
HN |
|
N |
|
|
|
N |
|
N |
N |
|
H |
||
|
AEE 788 / Novartis
Fig. 1. Available molecular structure of anti-angiogenic kinase inhibitors in development.
322 K.-H. Thierauch & A. Chlistalla
F |
NH |
O
O
N
N O N
AZD2171 / Astra-Zeneca
F |
NH2 |
N |
N |
N |
|
|
|||
|
|
|
N |
|
|
|
|
H |
|
|
N |
O |
|
|
|
H |
|
|
|
CHIR258 / Chiron
N
N |
NH |
|
O |
H |
|
|
|
|
|
N |
O |
|
|
|
|
|
N |
N |
O |
|
|
H |
|
GW78034 (also named SB78034 and GW2286)
GlaxoSmithKline
N
H
O
N
H
SU5416 SUGEN / Pfizer
Fig. 1. (Continued ).
Kinase Inhibitors |
323 |
Fig. 2. Selectivity pattern of anti-angiogenic kinase inhibitors according to Fabian et al. (Ref. 34, with permission of the editors).
Table 2. Selectivity and cellular activity of anti-angiogenic kinase inhibitors in clinical development (IC50 [nM]).
|
|
|
|
|
|
|
Inhib. |
Inh. tumor |
|
|
|
|
|
|
|
|
|
endoth. |
cell |
|
|
Agent |
VEGFR2 |
PDGFR |
c-kit |
FGFR |
b-raf |
Others |
cell prolif. |
prolif. |
Ref. |
|
|
|
|
|
|
|
|
|
|
|
|
BAY 43-9006 |
90 |
60 |
70 |
600 |
20–40 |
|
1500 |
2600 |
80 |
|
(Sorafenib, |
|
|
|
|
|
|
|
|
|
|
Bayer) |
|
|
|
|
|
|
|
|
|
|
PTK787/ZK |
40 |
600 |
400 |
>10000 |
>10000 |
c-fms 600 |
60 |
> 100000 |
69, 81 |
|
222584 |
|
|
|
|
|
|
|
|
|
|
(Vatalanib, |
|
|
|
|
|
|
|
|
|
|
Novartis, |
|
|
|
|
|
|
|
|
|
|
Schering AG) |
|
|
|
|
|
|
|
|
|
|
SU11248 |
10 |
10 |
10–100 |
800 |
|
FLT-3 30 |
4 |
1000 |
82, 83 |
|
(Sunitinib, |
|
|
|
|
|
IGFR 2400 |
|
|
|
|
Pfizer) |
|
|
|
|
|
Src 600 |
|
|
|
|
ZD6474 |
40 |
|
|
|
>10000 |
EGFR 100 |
60 |
|
84 |
|
(Astra-Zeneca) |
|
|
|
|
|
Fyn 300 |
|
|
|
|
AG 13736 |
10 |
n.a. |
50 |
n.a. |
>10000 |
Fyn 1000 |
1 |
3000 |
unpub. KHT |
|
(Pfizer) |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Chlistalla .A & Thierauch .H-.K 324
|
|
|
|
Table 2. |
(Continued ). |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Inhib. |
Inh. tumor |
|
|
|
|
|
|
|
|
endoth. |
cell |
|
|
Agent |
VEGFR2 |
PDGFR |
c-kit |
FGFR b-raf Others |
cell prolif. |
prolif. |
Ref. |
||
|
|
|
|
|
|
|
|
|
|
AEE 788 |
80 |
300 |
800 |
|
EGFR 2 |
|
3000 |
85 |
|
(Novartis) |
|
|
|
|
c-src 60 |
|
|
|
|
AMG 706 |
5 |
200 |
10 |
|
Ret 100 |
|
|
86 |
|
(Amgen) |
|
|
|
|
|
|
|
|
|
AZD 2171 |
1 |
5 |
2 |
30 |
EGFR 1600 |
4 |
1000 |
87 |
|
(Astra-Zeneca) |
|
|
|
|
Src 130 |
|
|
|
|
|
|
|
|
|
InsR 700# |
|
|
|
|
BIBF1120 |
20 |
60 |
|
70 |
Lck 20 |
10 |
|
88 |
|
|
|
|
|
|
Src 150 |
|
|
89 |
|
Chir-258 |
10 |
27 |
2 |
8 |
FLt-3 1 |
|
|
|
|
|
|
|
|
|
CSF-1R 36 |
|
|
|
|
GW786034 |
|
|
|
|
Insr 2100 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
No data |
|
|
|
|
|
|
|
|
|
available |
|
|
|
|
|
|
|
|
|
SU5416 |
300 |
300 |
200 |
|
Insr 7000 |
400 |
|
90 unpub. KHT |
|
|
|
|
|
|
Flt-3 100 nM |
|
|
|
|
Inhibitors Kinase
325