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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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
No information available.
Summary of Clinical Use Click here for help
This compound was assessed in clinical trials for the treatment of several types of cancer. Click here to view the full list of PF-03084014 trials registered with ClinicalTrials.gov. A number of PF-03084014 clinical trials appear to have been stopped or withdrawn, apparently for business reasons. Notes against these trials state that there were no safety/efficacy concerns behind the decisions. Development for desmoid tumours [8] (a rare and aggressive soft tissue sarcoma) was continued by SpringWorks Therapeutics. There were no FDA-approved treatments for desmoid tumours at the time. Based on efficacy data coming from clinical trials [9], nirogacestat was granted FDA orphan designation for this indication in mid-2018. EMA orphan drug designation followed in late 2019. In 2023, the FDA accepted nirogacestat for priority review as a treatment option for locally invasive, soft tissue desmoid tumours, and this culminated in full approval in November of that year [6]. Nirogacestat (Ogsiveo) was the first approved drug to reach the clinic as a treatment for desmoid tumours.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT04195399 A Study of a New Drug, Nirogacestat, for Treating Desmoid Tumors That Cannot be Removed by Surgery Phase 2 Interventional Children's Oncology Group
NCT01981551 Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors/Aggressive Fibromatosis Phase 2 Interventional National Institutes of Health Clinical Center (CC)
NCT03785964 Nirogacestat for Adults With Desmoid Tumor/Aggressive Fibromatosis (DT/AF) Phase 3 Interventional SpringWorks Therapeutics, Inc. 4-5
NCT05348356 Nirogacestat in Ovarian Granulosa Cell Tumors Phase 2 Interventional SpringWorks Therapeutics, Inc.