Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C15H15FIN3O3 |
| Molecular Weight | 431.2008 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
OC[C@@H](O)CNC(=O)C1=C(NC2=C(F)C=C(I)C=C2)C=NC=C1
InChI
InChIKey=VIUAUNHCRHHYNE-JTQLQIEISA-N
InChI=1S/C15H15FIN3O3/c16-12-5-9(17)1-2-13(12)20-14-7-18-4-3-11(14)15(23)19-6-10(22)8-21/h1-5,7,10,20-22H,6,8H2,(H,19,23)/t10-/m0/s1
| Molecular Formula | C15H15FIN3O3 |
| Molecular Weight | 431.2008 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Optical Activity | UNSPECIFIED |
DescriptionCurator's Comment: description was created based on several sources, including
http://ar2014.merckgroup.com/management-report/fundamental-information-about-the-group/research-and-development-at-merck
Curator's Comment: description was created based on several sources, including
http://ar2014.merckgroup.com/management-report/fundamental-information-about-the-group/research-and-development-at-merck
Pimasertib) (N-[(2S)-2,3-dihydroxypropyl]-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide hydrochloride; AS703026), a highly selective, potent, ATP non-competitive allosteric inhibitor of MEK1/2. It binds to MEK1/2 in an allosteric site that is distinct from, yet in close proximity to, the ATP binding site. Binding to this allosteric site prevents the activation of MEK1/2. Pimasertib continues to be investigated in patients with NRAS mutant malignant melanoma in a Phase II trial. This drug was discontinued in a combination with SAR245409 for Phase II study in low-grade serous ovarian cancer. This decision was based on the results of a futility analysis, conducted by the IDMC, which indicated that the trial was no longer expected to achieve its objective of showing a meaningful difference between the efficacies of the combination compared with pimasertib alone. The further development of pimasertib in pancreatic cancer was also discontinued, as a Phase II study in this indication did not reach its primary endpoint of prolongation of progression-free survival
Originator
Approval Year
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
283.8 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26657199/ |
60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
261.83 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26657199/ |
60 mg 2 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
12.7 pg × eq/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27483391/ |
2 μg single, intravenous dose: 2 μg route of administration: Intravenous experiment type: SINGLE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
265 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27483391/ |
60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
774 ng × eq/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27483391/ |
60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1160.8 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26657199/ |
60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
952.1 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26657199/ |
60 mg 2 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
0.036 ng × eq × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27483391/ |
2 μg single, intravenous dose: 2 μg route of administration: Intravenous experiment type: SINGLE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
937 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27483391/ |
60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
5318 ng × eq × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27483391/ |
60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
3.019 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26657199/ |
60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
3.53 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26657199/ |
60 mg 2 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
3.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27483391/ |
2 μg single, intravenous dose: 2 μg route of administration: Intravenous experiment type: SINGLE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
6.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27483391/ |
60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
17 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27483391/ |
60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN |
Funbound
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
6.7% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27483391/ |
PIMASERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN |
Doses
| Dose | Population | Adverse events |
|---|---|---|
45 mg 2 times / day multiple, oral MTD Dose: 45 mg, 2 times / day Route: oral Route: multiple Dose: 45 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
|
45 mg 2 times / day multiple, oral Studied dose Dose: 45 mg, 2 times / day Route: oral Route: multiple Dose: 45 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: unknown Food Status: UNKNOWN Sources: |
DLT: Diarrhea... |
60 mg 2 times / day multiple, oral Studied dose Dose: 60 mg, 2 times / day Route: oral Route: multiple Dose: 60 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
DLT: Hypokalemia, Stomatitis... Dose limiting toxicities: Hypokalemia (grade 3, 33.3%) Sources: Stomatitis (33.3%) Muscle weakness (33.3%) |
30 mg 2 times / day multiple, oral Studied dose Dose: 30 mg, 2 times / day Route: oral Route: multiple Dose: 30 mg, 2 times / day Sources: |
unhealthy Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Sources: |
DLT: Retinal detachment... Dose limiting toxicities: Retinal detachment (grade 1, 33.3%) Sources: |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Diarrhea | grade 2, 100% DLT, Disc. AE |
45 mg 2 times / day multiple, oral Studied dose Dose: 45 mg, 2 times / day Route: oral Route: multiple Dose: 45 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: unknown Food Status: UNKNOWN Sources: |
| Muscle weakness | 33.3% DLT, Disc. AE |
60 mg 2 times / day multiple, oral Studied dose Dose: 60 mg, 2 times / day Route: oral Route: multiple Dose: 60 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| Stomatitis | 33.3% DLT, Disc. AE |
60 mg 2 times / day multiple, oral Studied dose Dose: 60 mg, 2 times / day Route: oral Route: multiple Dose: 60 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| Hypokalemia | grade 3, 33.3% DLT, Disc. AE |
60 mg 2 times / day multiple, oral Studied dose Dose: 60 mg, 2 times / day Route: oral Route: multiple Dose: 60 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| Retinal detachment | grade 1, 33.3% DLT, Disc. AE |
30 mg 2 times / day multiple, oral Studied dose Dose: 30 mg, 2 times / day Route: oral Route: multiple Dose: 30 mg, 2 times / day Sources: |
unhealthy Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Sources: |
PubMed
| Title | Date | PubMed |
|---|---|---|
| MEK inhibitors as a chemotherapeutic intervention in multiple myeloma. | 2013-03-22 |
|
| MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy. | 2011-01-15 |
|
| Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo. | 2010-05 |
Patents
Sample Use Guides
Pimasertib will be administered as oral capsule at a dose of 60 mg twice daily continuously. Treatment will consist of repeated 21-day cycles which will be continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever comes first.
Route of Administration:
Oral
| Substance Class |
Chemical
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6ON9RK82AL
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Validated (UNII)
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NCI_THESAURUS |
C69145
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NCI_THESAURUS |
C129825
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1236699-92-5
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44187362
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DB14904
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9498
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100000176282
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C84864
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CHEMBL2107832
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ZZ-116
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| Related Record | Type | Details | ||
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SALT/SOLVATE -> PARENT | |||
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EXCRETED UNCHANGED |
AMOUNT EXCRETED
FECAL
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EXCRETED UNCHANGED |
AMOUNT EXCRETED
URINE
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| Related Record | Type | Details | ||
|---|---|---|---|---|
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METABOLITE -> PARENT |
AUC STUDY
PLASMA
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PARENT -> METABOLITE |
MINOR
URINE
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METABOLITE -> PARENT |
MAJOR
FECAL; PLASMA; URINE
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PARENT -> METABOLITE |
MINOR
FECAL; PLASMA; URINE
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METABOLITE -> PARENT |
LESS THAN 1%
MAJOR
URINE
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METABOLITE -> PARENT | |||
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METABOLITE -> PARENT |
M554 was not formed in
liver microsomes of different species (human, mouse, rat, dog, monkey) (
MAJOR
PLASMA; URINE
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PARENT -> METABOLITE |
MINOR
FECAL
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| Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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| Volume of Distribution | PHARMACOKINETIC |
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INTRAVENOUS ADMINISTRATION |
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