PEXIDARTINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C20H15ClF3N5
Molecular Weight	417.815
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

FC(F)(F)C1=NC=C(CNC2=NC=C(CC3=CNC4=C3C=C(Cl)C=N4)C=C2)C=C1

InChI

InChIKey=JGWRKYUXBBNENE-UHFFFAOYSA-N

InChI=1S/C20H15ClF3N5/c21-15-6-16-14(10-28-19(16)29-11-15)5-12-2-4-18(26-7-12)27-9-13-1-3-17(25-8-13)20(22,23)24/h1-4,6-8,10-11H,5,9H2,(H,26,27)(H,28,29)

HIDE SMILES / InChI

Molecular Formula	C20H15ClF3N5
Molecular Weight	417.815
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Pexidartinib (PLX3397) is a small-molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Pexidartinib binds to and inhibits phosphorylation of stem cell factor receptor (KIT), colony-stimulating factor-1 receptor (CSF1R) and FMS-like tyrosine kinase 3 (FLT3), which may result in the inhibition of tumor cell proliferation and down-modulation of macrophages, osteoclasts and mast cells involved in the osteolytic metastatic disease. FDA has granted Breakthrough Therapy Designation to pexidartinib (PLX3397) for the treatment of tenosynovial giant cell tumor (TGCT) where surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. In addition to Breakthrough Therapy Designation, pexidartinib (PLX3397) has been granted Orphan Drug Designation by FDA for the treatment of pigmented villonodular synovitis (PVNS) and giant cell tumor of the tendon sheath (GCT-TS). It also has received Orphan Designation from the European Commission for the treatment of TGCT.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Stem cell growth factor receptor 53	Inhibitor 8,297	0.027 µM [IC50]
Macrophage colony stimulating factor receptor 24	Inhibitor 8,297	0.013 µM [IC50]
Tyrosine-protein kinase receptor FLT3 43	Inhibitor 8,297	0.16 µM [IC50]
Cell division cycle 2-like protein kinase 6 3	Inhibitor 8,297	0.14 µM [IC50]
Vascular endothelial growth factor receptor 2 104	Inhibitor 8,297	0.44 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Tenosynovial giant cell tumor 2	Primary	Phase III 656	PEXIDARTINIB
Pigmented villonodular synovitis 2	Primary	Phase III 656	PEXIDARTINIB
Giant cell tumors of the tendon sheath 2	Primary	Phase III 656	PEXIDARTINIB

C_max

Value	Dose	Co-administered	Analyte	Population
8625 ng/mL	400 mg 2 times / day steady-state, oral		PEXIDARTINIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
77465 ng × h/mL	400 mg 2 times / day steady-state, oral		PEXIDARTINIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
26.6 h	400 mg 2 times / day steady-state, oral		PEXIDARTINIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1%	400 mg 2 times / day steady-state, oral		PEXIDARTINIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
400 mg 2 times / day steady, oral Recommended	unhealthy, 44 years (range: 18-79 years) n = 61	Disc. AE: ALT increased, AST increased...
400 mg 2 times / day steady, oral Recommended	unhealthy, 44 years (range: 18-79 years) n = 61	Disc. AE: Hypertension, LDH increased...
5000 mg 1 times / day multiple, oral Studied dose	unhealthy, 60.6 years (range: 24-82 years) n = 4
1000 mg 1 times / day steady, oral MTD	unhealthy, 63 years (range: 40–82 years) n = 8
400 mg 2 times / day steady, oral Recommended	unhealthy	Other AEs: Hepatotoxicity...

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AEs

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AE	Significance	Dose	Population
Abdominal pain	3.3% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, 44 years (range: 18-79 years) n = 61
Dizziness	3.3% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, 44 years (range: 18-79 years) n = 61
ALT increased	all grades, 13% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, 44 years (range: 18-79 years) n = 61
AST increased	all grades, 13% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, 44 years (range: 18-79 years) n = 61
Bilirubin increased	all grades, 3.3% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, 44 years (range: 18-79 years) n = 61

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587 inducer 781	inhibitor 1,767		inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 810 CYP2C8 911 CYP2C19 1,478 UGT1A1 204 UGT1A4 77 UGT2B7 146 P-gp 1,461 MATE1 306 MATE2 263 OATP1B1 788 OATP1B3 706 OATP2B1 123 BCRP 699 OCT1 512 OCT2 647 BSEP 402	BSEP 52 UGT1A4 347 P-gp 1,537 OAT1 326 OAT3 339 OCT1 327 OCT2 355 OATP1B1 406 OATP1B3 350 OATP2B1 104 BCRP 561	CYP2B6 547

Drug as perpetrator

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Target	Modality	Activity
BSEP 403	inhibitor 3,277	no
OCT1 543	inhibitor 3,277	no
OCT2 648	inhibitor 3,277	no
BCRP 773	inhibitor 3,277	weak
CYP3A4 1,925	inhibitor 3,277	yes [IC50 16.7 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,737	substrate 3,367	major	yes (co-administration study)
BCRP 561	substrate 3,367	no
BSEP 52	substrate 3,367	no
OAT1 326	substrate 3,367	no
OAT3 339	substrate 3,367	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:145373	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:145373
ChemicalBook	CB22742977	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB22742977
MolPort	MolPort-039-193-825	https://www.molport.com/shop/molecule-link/MolPort-039-193-825
ZINC	ZINC000115705166	http://zinc15.docking.org/substances/ZINC000115705166

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PubMed

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Title	Date	PubMed
Translocation and expression of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides.	2007 Jun	17527089
Molecular pathways involved in synovial cell inflammation and tumoral proliferation in diffuse pigmented villonodular synovitis.	2010 Sep	20620241
Synovial colony-stimulating factor-1 mRNA expression in diffuse pigmented villonodular synovitis.	2011 May-Jun	21640049
Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.	2015 Jul 30	26222558
Colony-Stimulating Factor 1 Receptor Blockade Inhibits Tumor Growth by Altering the Polarization of Tumor-Associated Macrophages in Hepatocellular Carcinoma.	2017 Aug	28572167

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Patents

Sample Use Guides

In Vivo Use Guide

1000 mg per day for 2 weeks (dose split over morning and evening), then 800 mg per day for 22 weeks (dose split over morning and evening).

Route of Administration: Oral

In Vitro Use Guide

In vitro, a population doubling assay showed that the IC50 of pexidartinib (PLX3397) for CSF1-induced bone marrow–derived macrophages (M(CSF1)) was 22 nM. Marked suppression of CSF-1R phosphorylation in M(CSF1) cells could be achieved with PLX3397. In contrast, the same doses of PLX3397 showed no antiproliferation effect on Hepa1-6, MHCC97-H, HCCLM3, HepG2, HUVEC, T cells, fibroblasts cells, and CSF2-induced bone marrow–derived macrophages.

Substance Class	Chemical
Record UNII	6783M2LV5X
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

PEXIDARTINIB

Official Name

English

pexidartinib [INN]

Common Name

English

PLX3397

Code

English

Pexidartinib [WHO-DD]

Common Name

English

PLX-3397

Code

English

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Classification Tree

Code System

Code

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

Protein Kinase Inhibitor

NCI_THESAURUS

C1967

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Code System

Code

Type

Description

CHEBI

145373

PRIMARY

ChEMBL

CHEMBL3545158

PRIMARY

CAS

1029044-16-3

PRIMARY

SMS_ID

100000171886

PRIMARY

DAILYMED

6783M2LV5X

PRIMARY

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					L9DP834D1P

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METABOLIC ENZYME -> INHIBITOR

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					0UY97CSG1T

CYTOCHROME P450 2B6

METABOLIC ENZYME -> INDUCER

Amount:


					OVI08ABI5H

MAST/STEM CELL GROWTH FACTOR RECEPTOR KIT

TARGET -> INHIBITOR

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					PUO0521HZV

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Amount:

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					2VXO9I489U

MACROPHAGE COLONY-STIMULATING FACTOR 1 RECEPTOR

TARGET -> INHIBITOR

Qualification:

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Amount:

1.7 NANOMOLAR (average)

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Related Record

Type

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					6783M2LV5X

PEXIDARTINIB

ACTIVE MOIETY

Amount:


					6783M2LV5X

PEXIDARTINIB

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount	Parameters
Volume of Distribution	PHARMACOKINETIC	187 LITERS (average)	ORAL ADMINISTRATION SINGLE DOSE 400 mg (average) IN HEALTHY SUBJECTS

Tmax	PHARMACOKINETIC	2.5 hours [1.5 to 8] (average)	IN HEALTHY SUBJECTS ORAL ADMINISTRATION SINGLE DOSE 400 mg (average)

Biological Half-life	PHARMACOKINETIC	26.7 hours (average)	IN HEALTHY SUBJECTS SINGLE DOSE 400 mg (average) ORAL ADMINISTRATION

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator