MIRDAMETINIB

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 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

Molecular Formula	C16H14F3IN2O4
Molecular Weight	482.193
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/18952427https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=456780
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/20332327 | https://www.ncbi.nlm.nih.gov/pubmed/18952427

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 Target	Pharmacology	Potency
Dual specificity mitogen-activated protein kinase kinase 2 9 Target ID: CHEMBL2964 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18952427	Inhibitor 8297	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 8297	1.0 nM [Ki]
Dual specificity mitogen-activated protein kinase kinase 1 20 Target ID: CHEMBL3587 Sources: http://pubs.acs.org/doi/suppl/10.1021/ml300049d	Inhibitor 8297	0.6 nM [IC50]
Dual specificity mitogen-activated protein kinase kinase 2 9 Target ID: CHEMBL2964 Sources: http://cancerres.aacrjournals.org/content/64/7_Supplement/925.1	Inhibitor 8297	1.0 nM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/ct2/show/NCT02022982	Primary	Phase II 1132	Unknown Approved Use Unknown
Neurofibromatosis 1 Sources: https://clinicaltrials.gov/ct2/show/NCT02096471	Primary	Phase II 1132	Unknown Approved Use Unknown
Colorectal cancer 101 Sources: https://clinicaltrials.gov/ct2/show/NCT02039336	Primary	Phase II 1132	Unknown Approved Use Unknown
Melanoma 88 Sources: https://clinicaltrials.gov/ct2/show/NCT00147550	Primary	Phase II 1132	Unknown Approved Use Unknown
Breast cancer 434 Sources: https://clinicaltrials.gov/ct2/show/NCT00147550	Primary	Phase II 1132	Unknown Approved Use Unknown
Non-small cell lung cancer 206 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20332327	Primary	Phase II 1132	Unknown Approved Use Unknown
Colorectal cancer 101 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21516509	Primary	Phase II 1132	Unknown Approved Use Unknown
Neurofibromatosis 1 Sources: https://clinicaltrials.gov/ct2/show/NCT02096471	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
462 μg/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
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
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
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
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
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

AUC

Value	Dose	Analyte	Population
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
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
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
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
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
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

T_1/2

Value	Dose	Analyte	Population
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
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
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
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
7.7 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
4.7 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

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 n = 4 Health Status: unhealthy Condition: Advanced Cancers Sex: M+F Food Status: FASTED Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	Other AEs: Diarrhea, Blurred vision... Other AEs: Diarrhea (all grades, 3 patients) Blurred vision (all grades, 1 pt) ataxia (all grades, 1 pt) dizziness (all grades, 1 pt) Rash (all grades, 2 patients) Fatigue (all grades, 2 patients) Nausea (all grades, 1 pt) Gait disturbance (all grades, 1 pt) Visual disturbance (all grades, 2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/
10 mg 2 times / day multiple, oral (unknown) 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 n = 13 Health Status: unhealthy Condition: Advanced Cancers Sex: M+F Food Status: FED Population Size: 13 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 (unknown) 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 n = 7 Health Status: unhealthy Condition: Advanced Cancers Sex: M+F Food Status: UNKNOWN Population Size: 7 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 (unknown) 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 n = 6 Health Status: unhealthy Condition: Advanced Cancers Sex: M+F Food Status: UNKNOWN Population Size: 6 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 (unknown) 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 n = 13 Health Status: unhealthy Condition: NSCLC Sex: M+F Food Status: UNKNOWN Population Size: 13 Sources: https://pubmed.ncbi.nlm.nih.gov/20332327/	Disc. AE: Blurred vision, fatigue... Other AEs: Confusional state, Diarrhea... AEs leading to discontinuation/dose reduction: Blurred vision (1 pt) fatigue (1 pt) Hallucinations (1 pt) Other AEs: Confusional state (grade 3, 8%) Diarrhea (grade 3, 8%) Peripheral edema (grade 1-2, 15%) Epistaxis (grade 1-2, 15%) Dyspnea (grade 3, 8%) Nausea (grade 1-2, 38%) Rash (grade 3, 8%) Asthenia (grade 1-2, 8%) Dermatitis acneiform (grade 1-2, 8%) Myalgia (grade 1-2, 8%) Vomiting (grade 1-2, 38%) Dry mouth (grade 1-2, 15%) Dyspepsia (grade 1-2, 15%) Facial edema (grade 1-2, 15%) headache (grade 1-2, 8%) Weight gain (grade 1-2, 8%) Sources: https://pubmed.ncbi.nlm.nih.gov/20332327/
20 mg 2 times / day multiple, oral (unknown) 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 n = 6 Health Status: unhealthy Condition: Advanced Cancers Sex: M+F Food Status: UNKNOWN Population Size: 6 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 (unknown) 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 n = 5 Health Status: unhealthy Condition: Advanced Cancers Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/	Other AEs: Optic neuropathy, rash... Other AEs: Optic neuropathy (1 pt) rash (grade 3, 1 pt) unsteady gait (grade 3, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/20215549/
30 mg 2 times / day multiple, oral (unknown) 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 n = 6 Health Status: unhealthy Condition: Advanced Cancers Sex: M+F Food Status: UNKNOWN Population Size: 6 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
Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.	2009 May	19282848
Phosphorous dysregulation induced by MEK small molecule inhibitors in the rat involves blockade of FGF-23 signaling in the kidney.	2012 Jan	21976371
Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance.	2012 May 10	21996734
MEK and the inhibitors: from bench to bedside.	2013 Apr 12	23587417

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.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 04:18:35 GMT 2023` Edited by `admin` on `Sat Dec 16 04:18:35 GMT 2023`
Record UNII	86K0J5AK6M
Record Status	`Validated (UNII)`
Record Version

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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

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

Systematic Name

English

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

Systematic Name

English

mirdametinib [INN]

Common Name

English

PD 0325901

Common Name

English

PD 901

Common Name

English

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

Systematic Name

English

PD 03525901

Common Name

English

MIRDAMETINIB [USAN]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

655618