Sutent

Pfizer's SUTENT
SU11248 (sunitinib malate) 2007

Pfizer: SUTENT/SU11248 (sunitinib malate)
Zhion APRIL 2, 2006

SU11248 is a SUGEN compound. The activity of SU11248 has been
presented at American Society of Hematology Meeting, Dec. 7-11, 2001
Orlando, Florida. The abstract title is "Sugen compounds SU5416 and
SU11248 inhibit Flt3 Activity: Therapeutic Applications in AML."

SU11248 is a VEGFR/FGFR/PDGFR inhibitor. [3]

Small molecule synthetic tyrosine kinase inhbitors are divided into three
broad categories; (1) inhibitors of the epidermal growth factor receptor
tyrosine kinase family, (2) inhibitors of the split kinase domain receptor
kinase subgroup, and (3) inhibitors of tyrosine kinases from multiple
subgroups (e.g. Gleevec). SU11248 is a small molecule belonged to the
second category. [4]

FLT3 (fms-related tyrosine kinase/Flk2?Stk-2) is a receptor tyrosine
kinase (RTK) primarily expressed on hematopoietic cells. In blasts from
acute myelogenous leukemia (AML) patients, 2 classes of FLT3 activating
mutations have been found: internal tandem duplication (ITD) mutations
in the juxtamembrane domain and point mutations in the kinase domain
activation loop. TLT2-ITD mutations are the most common molecular
defect related to AML. Thus, FLT3-ITD is an attractive molecular target for
therapy. Sutent (SU11248) is a selective inhibitor with selectivity for split
kinase domain RTKs, including platelet-derived growth factor receptors,
vascular endotheloal growth factor receptors and KIT.

    Why Sutent (SU11248) is so interested?

Sutent (SU11248) also has potent activity against wild-type
FLT3(FLT-WT), FLT3-ITD, and FLT3 activationloop (FLT3-Asp835) mutants
in phosphorylation assays. Sutent (SU11248) inhibits FLT3-driven
phosphorylation and induces apoptosis in vitro!! In addition, SU11248
inhibits FLT3-induced VEGF production.

One study has shown that Sutent (SU11248) could dramatically
regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model
and prolonged survival in the bone marrow engraftment model. [5]

Another report suggests that Sutent (SU11248) exhibits broad and
potent antitumor activity causing regression, growth arrest, or
substantially reduced growth of VARIOUS established xenografts derived
from human or rat tumor cell lines. [6]

      Why is targeted therapy so important?

Targeted therapy is directed against cancer-specific molecules and
signaling pathways and thus has more limited non-specific toxicities.

      Why is tyrosine kinases so important?

Tyrosine kinases play an important role in the modulation of growth factor
signaling. Tyrosine kinase Inibitors (TKIs) compete with the ATP binding
site of the catalytic domain of several oncogenic tyrosine kinases. TKIs
include imatinib mesylate (ST1571, Gleevec), gefitinib(Iressa), erlotinib
(OSI-1774, Tarceva), lapatinib (GW-572016), canertinib (CI1033),
semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY
43-9006), leflunomide (SU101) and sutent (SU11248). [7]

----------------------------------------NEWS----------------------------------------------
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Sutent (SU11248) pill is developed to treat gastrointestinal stromal
tumors, a type of stomach cancer, and kidney cancer that has spread to
other parts of the body and not been controlled by standard treatments.
Sutent might have significant advantages over existing treatments. [1]

For instance, new study shows Pfizer's SUTENT/SU11248 (sunitinib
malate) extends overall survival in Gleevec-resistant GIST. [2]

Sutent is one of the first in a new class of drugs that selectively targets
multiple protein receptors, called receptor tyrosine kinases. Tyrosine
kinases may be a molecular switch for cancer growth. Inhibition of these
tyrosine kinases is believed to starve tumors of blood and nutrients
needed for growth and simultaneously kill the cancer cells that make up
tumors.

Does Sutent have side effects?
The major side effects of Sutent are hypertension, fatigue and diarrhea.
[7]
                  FIGHT AGAINST CANCER

          ALL RIGHTS RESERVED 2007 zhion.

-REFEENCE-
[1] Pfizer Submits Application for Sutent to FDA PR Wed Aug 10, 2005 [2] New data
show Pfizer's SUTENT/SU11248 (sunitinib malate) extends overall survival in
Gleevec-resistant GIST Globandmail.com Aug 10, 2005 [3] US patent Application
no. 20050125054 [4] Laird AD et al Small molecule tyrosine kinase inhibitors:
clinical development of anticancer agents. Expert Opin Investig Drugs 2003
Jan;12(1):51-64. [5] O'Farrell AM et al, SU11248 is a novel FLT3 tyrosine kinase
inhibitor with potent activity in vitro and in vivo Blood 2003 May 1;101(9):3597-605
Epub2003 Jan 16. [6] Mendel DB et al, In vivo antitumor activity of SU11248, a
novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and
platelet-derived growth factor receptors: determination of a
pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 2003
Jan;9(1):327-37. [7] Pfizer, Wyeth Drugs Benefit Kidney-Cancer paients
(updated1) Bloomberg.com June 6 2006.

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NEWS:
In two large international studies, Sutent was given as initial treatment for advance kidney
cancer and helped patients live longer.Previously, Sutent was approved to help people who fail
a first therapy. ...[7]

Pfizer Inc. won US approval today to sell Sutent for fighting two hard-to-treat cancers of the
kidney and stomach. The FDA approved Sutent for treating GIST patients whose disease has
worsened after treatment with Novartis AG's Gleevec, or who cannot tolerate Gleevec.
Comparing to older generation of cancer drugs, Sutent is gentler on patients which may cause
less severe nausea and other harsh side effects. Sutent will cost about $37,713 per year.
---FDA approves Pfizer drug for two cancers, Reuters, January 26, 2006.