nirogacestat   Click here for help

GtoPdb Ligand ID: 7746

Synonyms: Ogsiveo® | PF-03084014 | PF3084014 | Z-3181
Approved drug
nirogacestat is an approved drug (FDA (2023))
Compound class: Synthetic organic
Comment: Nirogacestat (PF-3084014) is compound 14f in [2] where it is described as a centrally active γ-secretase inhibitor. It is a reversible, non-competitive, and orally bioactive agent. It was proposed an an anti-tumour agent [1,3,10-11].
PF-3084014 was also reported as an inhibitor of the NOTCH signalling pathway which bolstered its oncology credentials [7,10], since NOTCH inhibition promotes cell cycle arrest and induces apoptosis in tumour cells.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Click here for structure editor
Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 5
Hydrogen bond donors 3
Rotatable bonds 12
Topological polar surface area 70.98
Molecular weight 489.33
XLogP 5.14
No. Lipinski's rules broken 2
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES CCCC(C(=O)Nc1ncn(c1)C(CNCC(C)(C)C)(C)C)NC1CCc2c(C1)c(F)cc(c2)F
Isomeric SMILES CCC[C@@H](C(=O)Nc1ncn(c1)C(CNCC(C)(C)C)(C)C)N[C@H]1CCc2c(C1)c(F)cc(c2)F
InChI 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
InChI Key VFCRKLWBYMDAED-REWPJTCUSA-N
References
1. Arcaroli JJ, Quackenbush KS, Purkey A, Powell RW, Pitts TM, Bagby S, Tan AC, Cross B, McPhillips K, Song EK et al.. (2013)
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.
Br J Cancer, 109 (3): 667-75. [PMID:23868008]
2. Brodney MA, Auperin DD, Becker SL, Bronk BS, Brown TM, Coffman KJ, Finley JE, Hicks CD, Karmilowicz MJ, Lanz TA et al.. (2011)
Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: discovery of PF-3084014.
Bioorg Med Chem Lett, 21 (9): 2637-40. [PMID:21269827]
3. Federman N. (2022)
Molecular pathogenesis of desmoid tumor and the role of γ-secretase inhibition.
NPJ Precis Oncol, 6 (1): 62. [PMID:36068332]
4. Gounder M, Ratan R, Alcindor T, Schöffski P, van der Graaf WT, Wilky BA, Riedel RF, Lim A, Smith LM, Moody S et al.. (2023)
Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.
N Engl J Med, 388 (10): 898-912. [PMID:36884323]
5. Gounder MM, Atkinson TM, Bell T, Daskalopoulou C, Griffiths P, Martindale M, Smith LM, Lim A. (2023)
GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS©): psychometric properties and clinically meaningful thresholds as assessed in the Phase 3 DeFi randomized controlled clinical trial.
Qual Life Res, 32 (10): 2861-2873. [PMID:37347393]
6. Kingwell K. (2024)
γ-secretase inhibitor notches first approval.
Nat Rev Drug Discov, 23 (1): 9. [PMID:38057455]
7. López-Guerra M, Xargay-Torrent S, Rosich L, Montraveta A, Roldán J, Matas-Céspedes A, Villamor N, Aymerich M, López-Otín C, Pérez-Galán P et al.. (2015)
The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.
Leukemia, 29 (1): 96-106. [PMID:24781018]
8. Rohail S, Fareed A, Taimuri MA, Adnan A. (2023)
Nirogacestat and its potential impact on desmoid tumor.
Rare Tumors, 15: 20363613231182485. [PMID:37325381]
9. Sidaway P. (2023)
Nirogacestat effective in desmoid tumours.
Nat Rev Clin Oncol, 20 (5): 284. [PMID:36997640]
10. Wei P, Walls M, Qiu M, Ding R, Denlinger RH, Wong A, Tsaparikos K, Jani JP, Hosea N, Sands M et al.. (2010)
Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design.
Mol Cancer Ther, 9 (6): 1618-28. [PMID:20530712]
11. Zhang CC, Pavlicek A, Zhang Q, Lira ME, Painter CL, Yan Z, Zheng X, Lee NV, Ozeck M, Qiu M et al.. (2012)
Biomarker and pharmacologic evaluation of the γ-secretase inhibitor PF-03084014 in breast cancer models.
Clin Cancer Res, 18 (18): 5008-19. [PMID:22806875]