| Description |
Dabrafenib Mesylate is a potent and selective Raf kinase inhibitor
with IC50s of 0.6 and 5.0 nM for RafV600E and c-Raf, respectively. |
| Related Catalog |
Signaling Pathways >>
MAPK/ERK Pathway >>
Raf
Research Areas >>
Cancer
|
| Target |
BRafV600E:0.6 nM (IC50)
CRAF:5 nM (IC50)
|
| In Vitro |
Dabrafenib (GSK2118436, 1 μM) with 0.01 μM GSK1120212 inhibits
more than 90% of cell growth in the NRAS mutant clones. GSK2118436 is
sufficient to reduce S6P phosphorylation in A375[1]. Dabrafenib
suppresses the PolyP-mediated vascular barrier permeability,
upregulation of inflammatory biomarkers, adhesion/migration of
leukocytes, and activation and/or production of nuclear factor-κB, tumor
necrosis factor-α, and interleukin-6[2]. Dabrafenib inhibits the
release of HMGB1 and downregulates HMGB1-dependent inflammatory
responses by enhancing the expressions of cell adhesion molecules (CAMs)
in human endothelial cells[3].
|
| In Vivo |
Dabrafenib-treated females have mostly immature reproductive
tracts with no evidence of ovulation, similar to age-matched controls;
however, DAB-treated females have keratinized and histologically open
vaginas[5].
|
| Cell Assay |
For longer term proliferation assays, cells are plated and treated
with compound or combination of compounds in RMPI-1640 containing 10%
FBS for 12 days. Compound treatments are replaced at least once during
the assay. After 12 days, cells are stained with 0.5% methylene blue in
50% ethanol. Images are captured using flatbed scanner.
|
| Animal Admin |
The rat pups selected as the test system are derived from 26
10-week-old, time-mated, virus-antibody-free SD (Crl:CD[SD]) female
rats. Mated females are observed for natural deliveries from Day 20 to
23 pc (day parturition completed is designated PND 0). Litter
examinations are conducted when parturition is complete, on PNDs 3 and
6, and included gender identification, individual pup weights, and
external morphologic examinations. Parturient dams and their litters are
selected for study based on clinical signs and body weights, and
selected dams and their litters are randomized into study groups based
on clinical observations and PND 3 litter mean body weights. On PND 3 or
4, litters are culled to four males and five females, with minimal
fostering only when necessary to obtain the desired sex ratio, such that
natural litters are maintained as much as possible. Records are kept of
fostered pups of original and foster dams. All pups are identified by
paw tattoo. To the extent possible, nonlittermates are assigned to
subsets. DAB is formulated as a suspension in vehicle, 0.5%
hydroxypropylmethylcellulose K15M, and 0.1% (v/v) Tween80 in purified
water, and is given to juvenile male and female rats orally by gavage at
a dose volume of 5 ml/kg, based on daily body weight.
|
| References |
[1]. Greger
JG, et al. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome
acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib,
mediated by NRAS or MEK mutations. Mol Cancer Ther, 2012, 11(4),
909-920. [2]. Lee
S, et al. Anti-inflammatory effects of dabrafenib on
polyphosphate-mediated vascular disruption. Chem Biol Interact. 2016 Jul
22. [3]. Jung B, et al. Anti-septic effects of dabrafenib on HMGB1-mediated inflammatory responses. BMB Rep. 2016 Apr;49(4):214-9. [4]. Alexander
M Menzies, et al. Dabrafenib and its potential for the treatment of
metastatic melanoma. Drug Des Devel Ther. 2012; 6: 391–405. [5]. Posobiec
LM, et al. Early Vaginal Opening in Juvenile Female Rats Given
BRAF-Inhibitor Dabrafenib Is Not Associated with Early Physiologic
Sexual Maturation. Birth Defects Res B Dev Reprod Toxicol. 2015
Dec;104(6):244-52.
|
China
![N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide structure](https://www.chemsrc.com/caspic/004/1195768-20-7.png)
CAS#:1195768-18-3
