| Identification | Back Directory | [Name]
XL518 | [CAS]
934660-93-2 | [Synonyms]
XL518
RG7420
CS-1977
GDC-0973
CobiMetinib
GDC-0973/RG7420
XL518 ,GDC-0973
XL518 USP/EP/BP
GDC-0973(XL-518)
Cobimetinib(XL518)
Cobimetinib, >=98%
XL518, Co bimetinib
Cobimetinib,GDC-0973
GDC-0973 (Cobimetinib)
GDC0973, XL518, Cobimetinib
Cobimetinib (GDC-0973,XL 518)
Cobimetinib (GDC-0973, RG7420)
XL-518;GDC 0973 (XL518);COBIMETINIB;GDC0973;XL-518;XL 518;GDC 0973
1-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoyl]-3-[(2S)-2-piperidinyl]-3-azetidinol
[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone
(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylaMino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)Methanone
[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)aMino]phenyl][3-hydroxy-3-[(2S)-2-piperidinyl]-1-azetidinyl]Methanone
Methanone, [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)aMino]phenyl][3-hydroxy-3-(2S)-2-piperidinyl-1-azetidinyl]-
[3,4-Bis(Fluoranyl)-2-[(2-Fluoranyl-4-Iodanyl-Phenyl)amino]phenyl]-[3-Oxidanyl-3-[(2s)-Piperidin-2-Yl]azetidin-1-Yl]methanone | [Molecular Formula]
C21H21F3IN3O2 | [MDL Number]
MFCD22124461 | [MOL File]
934660-93-2.mol | [Molecular Weight]
531.31 |
| Chemical Properties | Back Directory | [Melting point ]
165 - 166°C | [Boiling point ]
565.9±50.0 °C(Predicted) | [density ]
1.706 | [storage temp. ]
Refrigerator | [solubility ]
Chloroform (Slightly), DMSO (Slightly), Ethyl Acetate (Slightly), Methanol (Slightly) | [form ]
Solid | [pka]
13.13±0.20(Predicted) | [color ]
Off-White |
| Hazard Information | Back Directory | [Description]
Cobimetinib, codeveloped by
Genentech and Exelixis, was approved in August 2015 in
Switzerland and November 2015 in the U.S. and Europe for the
treatment of unresectable or metastatic BRAFV600 mutationpositive
melanoma when used in combination with vemurafenib. Cobimetinib is a potent, highly selective reversible
inhibitor of mitogen-activated protein kinases (MEK) 1 and
2,120 which serves to inhibit phosphorylation of ERK1/2,121
disrupting the MAPK pathway which is responsible for cell
proliferation, cell survival, and migration.122 Combination of
cobimetinib with vemurafenib, an important BRAF inhibitor,123
enables targeting of multiple points on the MAPK pathway,
leading to overall enhanced tumor cell apoptosis and response
as compared to stand-alone treatment with vemurafenib.124
Specifically, in a representative trial of previously untreated
patients with BRAFV600 mutation-positive, unresectable, stage
IIIc or IV melanoma, combination of these two therapies led to
a significantly improved progression-free survival and overall
response rate versus patients treated only with vemurafenib. | [Uses]
A potent, selective, orally bioavailable inhibitor of MEK1, a component of the RAS/RAF/MEK/ERK pathway. It inhibits proliferation and stimulates apoptosis in a variety of human tumor cell lines. In preclinical xenograft models, oral administration of XL518 results in sustained inhibition of pERK in tumor tissue, but not brain tissue, leading to tumor growth inhibition and regression at well tolerated doses. | [Definition]
ChEBI: Cobimetinib is a member of the class of N-acylazetidines obtained by selective formal condensation of the carboxy group of 3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid with the secondary amino group from the azetidine ring of 3-[(2S)-piperidin-2-yl]azetidin-3-ol. An inhibitor of mitogen-activated protein kinase that is used (as its fumarate salt) in combination with vemurafenib for the treatment of patients with unresectable or metastatic melanoma. It has a role as an EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor and an antineoplastic agent. It is a member of piperidines, a N-acylazetidine, a tertiary alcohol, an aromatic amine, a secondary amino compound, a difluorobenzene and an organoiodine compound. It is a conjugate base of a cobimetinib(1+). | [Brand name]
Cotellic | [General Description]
Class: dual threonine/tyrosine kinase;
Treatment: melanoma with BRAF mutations; Other name: GDC-0973, XL518;
Oral bioavailability = 46%;
Elimination half-life = 44 h;
Protein binding = 95% | [Pharmacokinetics]
Cobimetinib has only moderate oral
bioavailability (46%), likely due to metabolism rather
than incomplete absorption. However, it displays
prolonged elimination half-life (44 h), which supports
a once-daily dosing regimen (60 mg). Following oral administration, the unchanged
cobimetinib and metabolite 4 were the major
circulating components in the plasma up to 48 hours
post dose (AUC0–48), accounting for 21% and 18% of
all the circulating drug-related components,
respectively (Fig. 4).
 | [Clinical Use]
Protein kinase inhibitor:
Treatment of unresectable or metastatic melanoma
with a BRAF V600 mutation in combination with
vemurafenib | [Synthesis]
Structurally, cobimetinib features an interesting azetidinol
substructure appended to the 2-position of a piperidine,
rendering the 2-carbon of the piperidine as a stereogenic
center bearing the (S)-configuration. While the early discovery
routes to cobimetinib relied on a piperidine resolution-based
route for accessing the cobimetinib core, the scale route
to this drug employs an impressive N-cyanomethyl oxazolidine
chiral auxiliary-mediated sequence to induce strereocontrol,
generating the requisite stereocenter with excellent selectivity
and requiring no chromatographic purification in the overall
synthetic sequence. Toward this end, the most likely scale
synthetic approach was initiated with deprotonation of
commercially available (3S,5R,8aS)-3-phenyl-hexahydrooxazolo[
3,2-a]pyridine-carbonitrile (180), followed
by addition of commercial 3-oxo-azetidine-1-carboxylic acid
tert-butyl ester (181), yielded 182 in high purity (92%) after
distillation and providing a rapid route to the core structure of
cobimetinib. One-pot ring opening and reduction of 182 was
accomplished by exposing this hemiaminal to acetic acid and
sodium cyanoborohydride, giving rise to intermediate 183. This
carbamate could be further reacted with aqueous HCl in
toluene to liberate the azetidine amine salt in high purity
(97.6%), which underwent immediate acylation with commercially
available 2,3,4-trifluoro-benzoyl chloride (184) to enable
formation of intermediate 185 in 85% purity after aqueous
workup. Reductive cleavage of the chiral auxiliary of 185 with
Pd/C and H2 under aqueous acidic conditions (AcOH, aq
HCl) yielded the desired piperidine amine, which could be
isolated as a solid (99.6% pure) after trituration with aqueous
HCl. Finally, aromatic fluoride substitution with commercially
available aniline 186 under basic conditions provided
cobimetinib in 99.7% purity after slow precipitation from
toluene (it is important to note that the authors offer no
comment as to the regioselectivity of this aromatic substitution
reaction). While the drug reportedly exists as a fumarate salt,
no synthetic reports describing the conversion of cobimetinib to the corresponding fumarate salt were available in the
chemical literature to our knowledge at the time of publication.
| [target]
Primary target: MEK1/2 | [Drug interactions]
Potentially hazardous interactions with other drugs
Antifungals: concentration increased by itraconazole.
Antipsychotics: increased risk of agranulocytosis -
avoid. | [Metabolism]
Metabolised by oxidation by CYP3A and glucuronidation
by UGT2B7. Extensively metabolised and eliminated in
faeces | [storage]
Store at RT |
| Questions And Answer | Back Directory | [Binding Mode]
Cobimetinib binds to a specific allosteric pocket
adjacent to the ATP site of MEK1, forming a highly
complex network of interactions involving the
terminal aminoethanol moiety with both the catalytic
loop Asp190 and the ATP γ-phosphate (Figs. 2
and 3). The amide oxygen hydrogen bonds to the
primary amine of Lys97. The piperidine nitrogen
approaches the catalytic loop, thereby enabling
interactions with both γ-phosphoryl oxygen of ATP
and the carboxylic acid residue of Asp190. The
azetidine hydroxyl also engages in interactions with
Asp190 and the γ-phosphoryl oxygen of ATP.
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