NIROGACESTAT

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C27H41F2N5O
Molecular Weight	489.6441
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCC[C@H](N[C@H]1CCC2=C(C1)C(F)=CC(F)=C2)C(=O)NC3=CN(C=N3)C(C)(C)CNCC(C)(C)C

InChI

InChIKey=VFCRKLWBYMDAED-REWPJTCUSA-N

InChI=1S/C27H41F2N5O/c1-7-8-23(32-20-10-9-18-11-19(28)12-22(29)21(18)13-20)25(35)33-24-14-34(17-31-24)27(5,6)16-30-15-26(2,3)4/h11-12,14,17,20,23,30,32H,7-10,13,15-16H2,1-6H3,(H,33,35)/t20-,23-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C27H41F2N5O
Molecular Weight	489.6441
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://adisinsight.springer.com/drugs/800025563
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/20363853 | https://www.ncbi.nlm.nih.gov/pubmed/24919951 | https://www.ncbi.nlm.nih.gov/pubmed/21269827

Nirogacestat (PF-3084014) is a tetralin imidazole gamma-secretase inhibitor. Gamma-secretase, a proteolytic enzyme complex, mediates processing of several integral membrane proteins including amyloid precursor protein and Notch. This compound can inhibit both Notch-related pathway in neoplasia and reduces amyloid-β production. Nirogacestat (PF-3084014) is under development by Pfizer for the treatment of cancer.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Gamma-secretase 21 Target ID: CHEMBL2094135 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20363853	Inhibitor 8504		1.2 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Aggressive Fibromatosis 2 Sources: http://adisinsight.springer.com/drugs/800025563	Primary	Phase II 1147	Unknown Approved Use Unknown
Pancreatic cancer 98 Sources: http://adisinsight.springer.com/drugs/800025563	Primary	Phase II 1147	Unknown Approved Use Unknown
Breast cancer 432 Sources: http://adisinsight.springer.com/drugs/800025563	Primary	Phase II 1147	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
963 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27906684	100 mg 2 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:		NIROGACESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
330 mg 2 times / day multiple, oral Highest studied dose Dose: 330 mg, 2 times / day Route: oral Route: multiple Dose: 330 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25231399	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/25231399	DLT: Skin rash... Disc. AE: Palpitations, Oropharyngeal pain... Dose limiting toxicities: Skin rash (grade 3, 50%) AEs leading to discontinuation/dose reduction: Palpitations (grade 1, 50%) Oropharyngeal pain (grade 1, 50%) Sources: https://pubmed.ncbi.nlm.nih.gov/25231399
220 mg 2 times / day multiple, oral MTD Dose: 220 mg, 2 times / day Route: oral Route: multiple Dose: 220 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25231399	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/25231399	DLT: Diarrhea... Dose limiting toxicities: Diarrhea (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/25231399
150 mg 2 times / day multiple, oral Studied dose Dose: 150 mg, 2 times / day Route: oral Route: multiple Dose: 150 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28350521	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/28350521	Disc. AE: Nausea, Diarrhea... AEs leading to discontinuation/dose reduction: Nausea (grade 2, 5.9%) Diarrhea (grade 2, 5.9%) Allergic urticaria (5.9%) Maculopapular rash (grade 2, 5.9%) Sources: https://pubmed.ncbi.nlm.nih.gov/28350521

AEs

AE	Significance	Dose	Population
Oropharyngeal pain	grade 1, 50% Disc. AE	330 mg 2 times / day multiple, oral Highest studied dose Dose: 330 mg, 2 times / day Route: oral Route: multiple Dose: 330 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25231399	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/25231399
Palpitations	grade 1, 50% Disc. AE	330 mg 2 times / day multiple, oral Highest studied dose Dose: 330 mg, 2 times / day Route: oral Route: multiple Dose: 330 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25231399	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/25231399
Skin rash	grade 3, 50% DLT	330 mg 2 times / day multiple, oral Highest studied dose Dose: 330 mg, 2 times / day Route: oral Route: multiple Dose: 330 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25231399	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/25231399
Diarrhea	grade 3, 16.7% DLT	220 mg 2 times / day multiple, oral MTD Dose: 220 mg, 2 times / day Route: oral Route: multiple Dose: 220 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25231399	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/25231399
Allergic urticaria	5.9% Disc. AE	150 mg 2 times / day multiple, oral Studied dose Dose: 150 mg, 2 times / day Route: oral Route: multiple Dose: 150 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28350521	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/28350521
Diarrhea	grade 2, 5.9% Disc. AE	150 mg 2 times / day multiple, oral Studied dose Dose: 150 mg, 2 times / day Route: oral Route: multiple Dose: 150 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28350521	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/28350521
Maculopapular rash	grade 2, 5.9% Disc. AE	150 mg 2 times / day multiple, oral Studied dose Dose: 150 mg, 2 times / day Route: oral Route: multiple Dose: 150 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28350521	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/28350521
Nausea	grade 2, 5.9% Disc. AE	150 mg 2 times / day multiple, oral Studied dose Dose: 150 mg, 2 times / day Route: oral Route: multiple Dose: 150 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28350521	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/28350521

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1087 substrate 1946 inhibitor 2252	inhibitor 2438	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 2153 CYP2C19 2057 CYP3A 227 P-gp 1741	CYPs 33 rP-gp 2

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
P-gp 1932	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363678166	inconclusive [IC50 8.1995 uM]
CYP1A2 2333	inhibitor 4027 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	no
CYP2D6 2546	inhibitor 4027 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	weak [IC50 13.5 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	weak [IC50 18.5 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	weak [IC50 20.3 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	weak [Ki 2.2 uM]
CYP3A 317	inhibitor 4027 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	yes [IC50 4.6 uM]	yes (co-administration study) Comment: Increased midazolam AUCinf and Cmax by 58.9% and 30.7% Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0
CYP3A4 2633	inducer 1966 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	yes
P-gp 1932	supressor 160 Sources: https://pubmed.ncbi.nlm.nih.gov/26202948/	yes

Drug as victim

Target	Modality	Activity
CYPs 33	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/23427934/	likely
rP-gp 2	substrate 4014 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	no
CYP3A4 1946	substrate 4014 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=10 Page: 10.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=11 Page: 11.0

PubMed

Title	Date	PubMed
Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors.	2015-11-15	26349011
Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer.	2015-10-15	26202948
Initial testing (stage 1) of the notch inhibitor PF-03084014, by the pediatric preclinical testing program.	2014-08	24664981
Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model.	2013-08-06	23868008
Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer.	2013-07-10	23402814
Biomarker and pharmacologic evaluation of the γ-secretase inhibitor PF-03084014 in breast cancer models.	2012-09-15	22806875
Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia.	2012-07	22504949
Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: discovery of PF-3084014.	2011-05-01	21269827
Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014.	2010-07	20363853
Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design.	2010-06	20530712

Sample Use Guides

In Vivo Use Guide

Dosage of Nirogacestat (PF-3084014) in phase II trial in adults with desmoid tumors/aggressive fibromatosis: orally at 150 mg twice a day in 21-day cycles

Route of Administration: Oral

In Vitro Use Guide

Nirogacestat (PF-3084014) can block Nicastrin/Notch4 axis and reverse epithelial to mesenchymal transition process in in MCF7 breast cancer cells.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 21:31:55 GMT 2025` Edited by `admin` on `Mon Mar 31 21:31:55 GMT 2025`
Record UNII	QZ62892OFJ
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

NIROGACESTAT

Official Name

English

nirogacestat [INN]

Preferred Name

English

PF-03084014

Code

English

(S)-2-(((S)-6,8-DIFLUORO-1,2,3,4-TETRAHYDRONAPHTHALEN-2-YL)AMINO)-N-(1-(2-METHYL-1-(NEOPENTYLAMINO)PROPAN-2-YL)-1H-IMIDAZOL-4-YL)PENTANAMIDE

Systematic Name

English

NIROGACESTAT [USAN]

Common Name

English

PENTANAMIDE, 2-(((2S)-6,8-DIFLUORO-1,2,3,4-TETRAHYDRO-2-NAPHTHALENYL)AMINO)-N-(1-(2-((2,2-DIMETHYLPROPYL)AMINO)-1,1-DIMETHYLETHYL)-1H-IMIDAZOL-4-YL)-, (2S)-

Systematic Name

English

(2S)-2-(((2S)-6,8-DIFLUORO-1,2,3,4-TETRAHYDRO-2-NAPHTHALENYL)AMINO)-N-(1-(2-((2,2-DIMETHYLPROPYL)AMINO)-1,1-DIMETHYLETHYL)-1H-IMIDAZOL-4-YL)PENTANAMIDE

Systematic Name

English

PF 3084014

Code

English

PF 03084014

Code

English

Nirogacestat [WHO-DD]

Common Name

English

PF-3084014

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

636518