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Details

Stereochemistry ABSOLUTE
Molecular Formula C16H14F3IN2O4
Molecular Weight 482.193
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of MIRDAMETINIB

SMILES

OC[C@@H](O)CONC(=O)C1=C(NC2=C(F)C=C(I)C=C2)C(F)=C(F)C=C1

InChI

InChIKey=SUDAHWBOROXANE-SECBINFHSA-N
InChI=1S/C16H14F3IN2O4/c17-11-3-2-10(16(25)22-26-7-9(24)6-23)15(14(11)19)21-13-4-1-8(20)5-12(13)18/h1-5,9,21,23-24H,6-7H2,(H,22,25)/t9-/m1/s1

HIDE SMILES / InChI

Description

PD 0325901 is an orally bioavailable, synthetic organic molecule targeting mitogen-activated protein kinase kinase (MAPK/ERK kinase or MEK) with potential antineoplastic activity. MEK inhibitor PD325901, a derivative of MEK inhibitor CI-1040, selectively binds to and inhibits MEK, which may result in the inhibition of the phosphorylation and activation of MAPK/ERK and the inhibition of tumor cell proliferation. Clinical trials of monotherapy PD0325901 agains non-small cell lung cancer and colorectal cancer did not reach efficacy end point. For subsequent studies KRAS-positive patients with non-small cell lung cancer and colorectal cancer were selected, and PD0325901 was evaluated in combination with pablociclib and dacomtinib. PD0325901 is evaluated in phase II clinical trials against neurofibromatosis.

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
1.0 nM [Ki]
1.0 nM [Ki]
0.6 nM [IC50]
1.0 nM [Ki]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown
Primary
Unknown
Primary
Unknown
Primary
Unknown
Primary
Unknown
Primary
Unknown
Primary
Unknown
Primary
Unknown

Cmax

ValueDoseCo-administeredAnalytePopulation
462 μg/mL
10 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
706 ng/mL
15 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
839 ng/mL
15 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
972 ng/mL
20 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
766 ng/mL
20 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
1640 ng/mL
30 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
198 ng/mL
4 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
1784 ng × h/mL
10 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
2840 ng × h/mL
15 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
3062 ng × h/mL
15 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
3235 ng × h/mL
20 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
3497 ng × h/mL
20 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
6215 ng × h/mL
30 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
691 ng × h/mL
4 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
7.28 h
10 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
8.7 h
15 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
5.2 h
15 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
4.6 h
20 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
7.7 h
20 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
4.7 h
30 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens
5.5 h
4 mg 2 times / day multiple, oral
PD-0325901 plasma
Homo sapiens

Doses

AEs

PubMed

Sample Use Guides

In Vivo Use Guide
In clinical trials against KRAS-mutant NSCLC PD-0325901 was administered orally twice daily, 3 weeks out of every 4 in each cycle. The initial dose for phase 1 of the study was be 2 mg twice daily.
Route of Administration: Oral
In Vitro Use Guide
MTT assay was used to evaluate effect of PD-0325901 on tumor cell proliferation. Briefly, cells (800/well) were seeded into a 96-well plate, and after 5 days of treatment with the indicated concentrations of PD0325901, 10 μL of 5 mg/mL MTT (Sigma) was added to cell culture, followed by addition of 100 μL of 10% sodium dodecyl sulfate (SDS) solution 4 hours later. After incubation for another 12 hours, the plates were read on a microplate reader at a test wavelength of 570 nm and a reference wavelength of 670 nm. PD-0325901 demonstrated potent inhibition of cells harboring BRAF or RAS mutations (KAK1, KAT5, KAT7, KAT10, NPA, DRO, and C643) with IC50 ranging from 0.059 to 0.783 uM.