Mirdametinib

Details

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

SHOW SMILES / InChI

Structure Search

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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/18952427
Curator's Comment: description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT02022982 | https://clinicaltrials.gov/ct2/show/NCT02096471 | https://clinicaltrials.gov/ct2/show/NCT00147550

PD-0325901 is an orally bioavailable inhibitor of mitogen-activated protein kinase kinases (MAPK/ERK kinases 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. PD-0325901 is tested in clinical trials against non-small cell lung cancer, neurofibromatosis, melanoma and breast cancer.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dual specificity mitogen-activated protein kinase kinase 2 10 Target ID: CHEMBL2964 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18952427	Inhibitor 8504		1.0 nM [Ki]
Dual specificity mitogen-activated protein kinase kinase 1 20 Target ID: CHEMBL3587 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18952427	Inhibitor 8504		1.0 nM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 211 Sources: https://clinicaltrials.gov/ct2/show/NCT02022982	Primary	Phase II 1147	Unknown Approved Use Unknown
Neurofibromatosis 1 Sources: https://clinicaltrials.gov/ct2/show/NCT02096471	Primary	Phase II 1147	Unknown Approved Use Unknown
Colorectal cancer 102 Sources: https://clinicaltrials.gov/ct2/show/NCT02039336	Primary	Phase II 1147	Unknown Approved Use Unknown
Melanoma 88 Sources: https://clinicaltrials.gov/ct2/show/NCT00147550	Primary	Phase II 1147	Unknown Approved Use Unknown
Breast cancer 432 Sources: https://clinicaltrials.gov/ct2/show/NCT00147550	Primary	Phase II 1147	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
19.9 ng/mL EXPERIMENT https://clincancerres.aacrjournals.org/content/16/6/1924.full-text.pdf	1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
706 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	15 mg 2 times / day multiple, oral dose: 15 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1640 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	30 mg 2 times / day multiple, oral dose: 30 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
198 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	4 mg 2 times / day multiple, oral dose: 4 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
839 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	15 mg 2 times / day multiple, oral dose: 15 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
766 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	20 mg 2 times / day multiple, oral dose: 20 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
972 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	20 mg 2 times / day multiple, oral dose: 20 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
462 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	10 mg 2 times / day multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
94.6 ng × h/mL EXPERIMENT https://clincancerres.aacrjournals.org/content/16/6/1924.full-text.pdf	1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2840 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	15 mg 2 times / day multiple, oral dose: 15 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
6215 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	30 mg 2 times / day multiple, oral dose: 30 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
691 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	4 mg 2 times / day multiple, oral dose: 4 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
3062 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	15 mg 2 times / day multiple, oral dose: 15 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
3497 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	20 mg 2 times / day multiple, oral dose: 20 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
3235 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	20 mg 2 times / day multiple, oral dose: 20 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1784 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	10 mg 2 times / day multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
18 h EXPERIMENT https://clincancerres.aacrjournals.org/content/16/6/1924.full-text.pdf	1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
8.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	15 mg 2 times / day multiple, oral dose: 15 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
4.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	30 mg 2 times / day multiple, oral dose: 30 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
5.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	4 mg 2 times / day multiple, oral dose: 4 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
5.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	15 mg 2 times / day multiple, oral dose: 15 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
7.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	20 mg 2 times / day multiple, oral dose: 20 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
4.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	20 mg 2 times / day multiple, oral dose: 20 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
7.28 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20215549/	10 mg 2 times / day multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:	PD-0325901 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
15 mg 2 times / day multiple, oral MTD Dose: 15 mg, 2 times / day Route: oral Route: multiple Dose: 15 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	unhealthy Health Status: unhealthy Sex: M+F Food Status: FASTED Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	Other AEs: Rash, Diarrhea... Other AEs: Rash (all grades, 2 patients) Diarrhea (all grades, 3 patients) Fatigue (all grades, 2 patients) Nausea (all grades, 1 pt) ataxia (all grades, 1 pt) dizziness (all grades, 1 pt) Gait disturbance (all grades, 1 pt) Visual disturbance (all grades, 2 patients) Blurred vision (all grades, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/
10 mg 2 times / day multiple, oral Studied dose Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	unhealthy Health Status: unhealthy Sex: M+F Food Status: FED Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	DLT: confusion... Dose limiting toxicities: confusion (grade 3, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/
10 mg 2 times / day multiple, oral Studied dose Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	unhealthy Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	DLT: Confusion, Dizziness... Dose limiting toxicities: Confusion (grade 3, 1 pt) Dizziness (grade 3, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/
15 mg 2 times / day multiple, oral Studied dose Dose: 15 mg, 2 times / day Route: oral Route: multiple Dose: 15 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	unhealthy Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	DLT: rash... Dose limiting toxicities: rash (grade 3, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/
15 mg 2 times / day multiple, oral Studied dose Dose: 15 mg, 2 times / day Route: oral Route: multiple Dose: 15 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20332327/	unhealthy Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/20332327/	Disc. AE: Blurred vision, fatigue... Other AEs: Diarrhea, Rash... AEs leading to discontinuation/dose reduction: Blurred vision (1 pt) fatigue (1 pt) Hallucinations (1 pt) Other AEs: Diarrhea (grade 3, 8%) Rash (grade 3, 8%) Dyspnea (grade 3, 8%) Confusional state (grade 3, 8%) Vomiting (grade 1-2, 38%) Nausea (grade 1-2, 38%) Dermatitis acneiform (grade 1-2, 8%) Peripheral edema (grade 1-2, 15%) Facial edema (grade 1-2, 15%) Dry mouth (grade 1-2, 15%) Myalgia (grade 1-2, 8%) Asthenia (grade 1-2, 8%) Weight gain (grade 1-2, 8%) headache (grade 1-2, 8%) Dyspepsia (grade 1-2, 15%) Epistaxis (grade 1-2, 15%) Sources: https://pubmed.ncbi.nlm.nih.gov/20332327/
20 mg 2 times / day multiple, oral Studied dose Dose: 20 mg, 2 times / day Route: oral Route: multiple Dose: 20 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	unhealthy Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	DLT: rash, Left ventricular ejection fraction decreased... Dose limiting toxicities: rash (grade 3, 1 pt) Left ventricular ejection fraction decreased (grade 3, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/
20 mg 2 times / day multiple, oral Studied dose Dose: 20 mg, 2 times / day Route: oral Route: multiple Dose: 20 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	unhealthy Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	Other AEs: rash, unsteady gait... Other AEs: rash (grade 3, 1 pt) unsteady gait (grade 3, 1 pt) Optic neuropathy (1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/
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: https://pubmed.ncbi.nlm.nih.gov/20215549/	unhealthy Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	DLT: rash, diarrhea... Dose limiting toxicities: rash (grade 3, 1 pt) diarrhea (grade 3, 1 pt) syncope (grade 3, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/

AEs

PubMed

Title	Date	PubMed
Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells.	2015-08-18	26284497
U0126, a mitogen-activated protein kinase kinase 1 and 2 (MEK1 and 2) inhibitor, selectively up-regulates main isoforms of CYP3A subfamily via a pregnane X receptor (PXR) in HepG2 cells.	2014-12	24819614
PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies.	2014-10-09	25119042
Pan-FGFR inhibition leads to blockade of FGF23 signaling, soft tissue mineralization, and cardiovascular dysfunction.	2013-10	23872713
Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories.	2013-04-15	23474388
MEK and the inhibitors: from bench to bedside.	2013-04-12	23587417
Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance.	2012-05-10	21996734
The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition.	2012-04-10	22415236
Phosphorous dysregulation induced by MEK small molecule inhibitors in the rat involves blockade of FGF-23 signaling in the kidney.	2012-01	21976371
Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.	2009-05	19282848
The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901.	2008-12-15	18952427

Patents

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.

Name

Type

Language

PD-0325901

Preferred Name

English

Mirdametinib

Official Name

English

Mirdametinib [WHO-DD]

Common Name

English

Benzamide, N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-

Systematic Name

English

N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide

Systematic Name

English

GOMEKLI

Brand Name

English

N-[((R)-2,3-Dihydroxypropyl)oxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide

Systematic Name

English

PD0325901

Code

English

mirdametinib [INN]

Common Name

English

PD-901

Code

English

(-)-N-(((R)-2,3-DIHYDROXYPROPYL)OXY)-3,4-DIFLUORO-2-((2-FLUORO-4-IODOPHENYL)AMINO)BENZAMIDE

Systematic Name

English

PD-03525901

Code

English

MIRDAMETINIB [USAN]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

655618