Refametinib (RDEA119, Bay 86-9766) 923032-37-5

.cp_wz table {border-top: 1px solid #ccc;border-left:1px solid #ccc; } .cp_wz table td{border-right: 1px solid #ccc; border-bottom: 1px solid #ccc; padding: 5px 0px 0px 5px;} .cp_wz table th {border-right: 1px solid #ccc;border-bottom: 1px solid #ccc; padding: 5px 0px 0px 5px;}


Molecular Weight:

572.34 Refametinib (RDEA119, Bay 86-9766) is a potent, ATP non-competitive and highly selective inhibitor of MEK1 and MEK2 with IC50 of 19 nM and 47 nM, respectively.


Biological Activity


RDEA119 is selectively bound directly to an allosteric pocket in the
MEK1/2 enzymes, and highly efficacious at inhibiting cell proliferation
in several tumor cell lines, including A375, SK-MEI-28, Colo205, HT-29
and BxPC3. RDEA119 inhibits anchorage-dependent growth of human cancer
cell lines harboring the gain-of-function V600E BRAF mutant with GI50
values ranging from 67 to 89 nM. Under anchorage-independent conditions,
GI50 values for all cell lines tested are similar (40-84 nM). RDEA119
shows a tissue selectivity that reduces its potential for central
nervous system–related side effects.


RDEA119 potently inhibits the
proliferation of the 4 cell lines that harbored BRAF mutation but has no
or modest effects on the other 4 cells that harbored wild-type BRAF
(IC50 of 0.034-0.217 μM vs. 1.413-34.120 μM). This inhibitory effect of
RDEA119 in selected cell lines OCUT1 (BRAF V600E(+), PIK3CA H1047R(+))
and SW1376 (BRAF V600E(+)) is enhanced by combination with the mTOR
inhibitor, temsirolimus. RDEA119 and temsirolimus also show synergistic
effects on autophagic death of OCUT1 and KAT18 cells selectively tested.


Oral administration of RDEA119 at 50 mg/kg on a once daily × 14 schedule
leads to a 68% tumor growth inhibition (TGI) in human melanoma A375
tumor model. Oral administration of RDEA119 at 25 mg/kg on a once a once
daily × 14 schedule leads to a 123% TGI in human colon carcinoma
Colo205 tumor model (TGI > 100% occurs when the tumor shrinks below
its starting volume). A dose of 25 mg/kg once daily × 14 produces 56%
and 67% TGI for HT-29 and A431 tumors, respectively.


Protocol(Only for Reference)


Kinase Assay:


[1]

MEK Kinase Assay

Kinase inactive murine ERK2 (mERK2) K52A/T183A is affinity purified from Escherichia coli expressed using the pET21a vector. MEK1 kinase activity is determined using mERK2 K52A T183A as the substrate. Recombinant MEK1 enzyme (5 nM) is first activated by 0.02 unit or 1.5 nM of RAF1 in the presence of 25 mM HEPES (pH 7.8), 1 mM MgCl2, 50 mM NaCl, 0.2 mM EDTA, and 50 μM ATP for 30 minutes at 25 °C. The reactions are initiated by adding 2 μM of mERK2K52A T183A and 2.5 μCi [γ-33P] ATP in a total volume of 20 μL. The MEK2 kinase activity is determined similarly except that activation by RAF1 is not needed and 11 nM of MEK2 enzyme (active) are used in the assays.Kinase profiling is performed by Invitrogen using their Select Screen Kinase Profiling Service. The Z'-LYTE biochemical assay is used. RDEA119 is assayed in quadruplicate at 10 μM against 205 kinases.

Cell Assay:


[1]

Cell lines	A375, SK-MEI-28, Colo205, HT-29 and BxPC3 cells
Concentrations	10-1000 nM
Incubation Time	48 hours
Method	For anchorage-dependent growth inhibition experiments, cells are plated in white 384-well plates at 1,000/20 μL/well or white 96-well microplates at 4,000/100 μL/well. After 24-h incubation at 37 °C, 5% CO2, and 100% humidity, RDEA119 is incubated for 48 hours at 37 °C and assayed using CellTiter-Glo. For the 96-well anchorage-independent growth assay, wells of an [ultralow binding" plate (Corning) are filled with 60 μL of a 0.15% agarose solution in complete RPMI 1640. Then, 60 μL of complete RPMI 1640 containing 9,000 cells in 0.15% agarose are added per well. After 24 hour, 60 μL of a 3 × drug solution in agarose-free complete RPMI 1640 are added. After 7 d, 36 μL of 6 × 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium, inner salt reagent are added per well. After 2 hours at 37 °C, absorbance at 490 nm is determined on the M5 plate reader.

Animal Study:


[1]

Animal Models	Female athymic nude mice are injected s.c. with A375, HT-29 and A431 tumor; male athymic nude mice with Colo205 tumor.
Formulation	RDEA119 is dissolved in saline.
Dosages	25 or 50 mg/kg
Administration	Orally once daily for 14 days

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse Km(3)	= 11.2 mg/kg
	rat Km(6)

Chemical Information

Molecular Weight (MW)	572.34
Formula	C19H20F3IN2O5S
CAS No.	923032-37-5

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms	BAY 869766

Solubility (25°C) *	In vitro	DMSO	100 mg/mL (174.72 mM)
		Water	<1 mg/mL (
		Ethanol	100 mg/mL (174.72 mM)
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Name	(S)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide

Molarity Calculator
Dilution Calculator
Molecular Weight Calculator

Contact us if you need more details on Refametinib 923032-37-5. We are ready to answer your questions on packaging, logistics, certification or any Other aspects about RDEA119 923032-37-5、Bay 86-9766 923032-37-5. If these products fail to match your need, please contact us and we would like to provide relevant information.

Product Categories : MAPK > MEK Inhibitor