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

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 8297		1.2 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Aggressive Fibromatosis 2 Sources: http://adisinsight.springer.com/drugs/800025563	Primary	Phase II 1132	Unknown Approved Use Unknown
Pancreatic cancer 97 Sources: http://adisinsight.springer.com/drugs/800025563	Primary	Phase II 1132	Unknown Approved Use Unknown
Breast cancer 434 Sources: http://adisinsight.springer.com/drugs/800025563	Primary	Phase II 1132	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 Page: p.62	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/25231399 Page: p.62	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 Page: p.62
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 Page: p.62	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/25231399 Page: p.62	DLT: Diarrhea... Dose limiting toxicities: Diarrhea (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/25231399 Page: p.62
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 Page: p.1565	unhealthy, ADULT n = 17 Health Status: unhealthy Condition: desmoid tumor Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 17 Sources: https://pubmed.ncbi.nlm.nih.gov/28350521 Page: p.1565	Disc. AE: Maculopapular rash, Nausea... AEs leading to discontinuation/dose reduction: Maculopapular rash (grade 2, 5.9%) Nausea (grade 2, 5.9%) Diarrhea (grade 2, 5.9%) Allergic urticaria (5.9%) Sources: https://pubmed.ncbi.nlm.nih.gov/28350521 Page: p.1565

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 Page: p.62	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/25231399 Page: p.62
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 Page: p.62	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/25231399 Page: p.62
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 Page: p.62	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/25231399 Page: p.62
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 Page: p.62	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/25231399 Page: p.62
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 Page: p.1565	unhealthy, ADULT n = 17 Health Status: unhealthy Condition: desmoid tumor Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 17 Sources: https://pubmed.ncbi.nlm.nih.gov/28350521 Page: p.1565
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 Page: p.1565	unhealthy, ADULT n = 17 Health Status: unhealthy Condition: desmoid tumor Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 17 Sources: https://pubmed.ncbi.nlm.nih.gov/28350521 Page: p.1565
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 Page: p.1565	unhealthy, ADULT n = 17 Health Status: unhealthy Condition: desmoid tumor Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 17 Sources: https://pubmed.ncbi.nlm.nih.gov/28350521 Page: p.1565
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 Page: p.1565	unhealthy, ADULT n = 17 Health Status: unhealthy Condition: desmoid tumor Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 17 Sources: https://pubmed.ncbi.nlm.nih.gov/28350521 Page: p.1565

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 substrate 1737 inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2C19 1478 CYP3A 214 P-gp 1461	CYPs 33 rP-gp 2

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363678166	inconclusive [IC50 8.1995 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	weak [IC50 13.5 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	weak [IC50 18.5 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	weak [IC50 20.3 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	weak [Ki 2.2 uM]
CYP3A 298	inhibitor 3277 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 1925	inducer 1573 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	yes
P-gp 1650	supressor 155 Sources: https://pubmed.ncbi.nlm.nih.gov/26202948/	yes

Drug as victim

Target	Modality	Activity
CYPs 33	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23427934/	likely
rP-gp 2	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=14 Page: 14.0	no
CYP3A4 1737	substrate 3367 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 1647	inhibitor 1626 Sources: https://www.clinicaltrials.gov/ProvidedDocs/51/NCT01981551/Prot_SAP_000.pdf#page=11 Page: 11.0

PubMed

Title	Date	PubMed
Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014.	2010 Jul	20363853
Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design.	2010 Jun	20530712
Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: discovery of PF-3084014.	2011 May 1	21269827
Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors.	2011 Nov 24	21995460
Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia.	2012 Jul	22504949
Biomarker and pharmacologic evaluation of the γ-secretase inhibitor PF-03084014 in breast cancer models.	2012 Sep 15	22806875
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 Aug 6	23868008
Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer.	2013 Jul 10	23402814
Initial testing (stage 1) of the notch inhibitor PF-03084014, by the pediatric preclinical testing program.	2014 Aug	24664981
The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.	2015 Jan	24781018
Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors.	2015 Nov 15	26349011
Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer.	2015 Oct 15	26202948

Patents

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.

Name

Type

Language

NIROGACESTAT

Official 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 [INN]

Common Name

English

Nirogacestat [WHO-DD]

Common Name

English

PF-3084014

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

636518