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Identification
- Summary
Nirogacestat is a gamma-secretase inhibitor used to treat desmoid tumors
- Brand Names
- Ogsiveo
- Generic Name
- Nirogacestat
- DrugBank Accession Number
- DB12005
- Background
Nirogacestat is a small-molecule gamma-secretase inhibitor that was investigated as a potential treatment for desmoid tumors. Desmoid tumors are typically characterized by aberrant activation in Notch signaling.1 Interaction between the notch receptors and their ligands activates proteolytic cleavage by gamma-secretase; therefore, the inhibition of gamma-secretase can potentially inhibit Notch signaling and thus impede the growth of desmoid tumors.2
Nirogacestat was approved under the brand name OGSIVEO on November 27, 2023, by the FDA for the treatment of adult patients with progressing desmoid tumors who require systemic treatment. It was previously granted breakthrough therapy, fast track, and orphan drug designations for the treatment of desmoid tumors, and the final approval was based on positive results obtained in the Phase 3 DeFi trial, where a confirmed objective response rate was observed to be 41% compared to 8% with the placebo.4
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Nirogacestat (DB12005)
- Weight
- Average: 489.656
Monoisotopic: 489.327917286 - Chemical Formula
- C27H41F2N5O
- Synonyms
- Nirogacestat
- External IDs
- PF-03084014
- PF-3084014
Pharmacology
- Indication
Nirogacestat is indicated for adult patients with progressing desmoid tumors who require systemic treatment.3
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Progressive desmoids tumors •••••••••••• ••••• ••••••• •••••••• ••••••• •••••• - Contraindications & Blackbox Warnings
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There is an exposure-response relationship between nirogacestat exposure and Grade 3 hypophosphatemia with a higher risk of Grade 3 hypophosphatemia at higher exposure.3
At the recommended dosage, a mean increase in the QTc interval > 20 ms was not observed.3
- Mechanism of action
Nirogacestat is a gamma secretase inhibitor that blocks proteolytic activation of the Notch receptor. When dysregulated, Notch can activate pathways that contribute to tumor growth.3
Target Actions Organism APresenilin-1 inhibitorHumans AGamma-secretase subunit PEN-2 modulatorHumans AGamma-secretase subunit APH-1A modulatorHumans APresenilin-2 inhibitorHumans - Absorption
The following pharmacokinetics parameters in patients with desmoid tumors were calculated as follows: Cmax (508 (62) ng/mL), AUC0-tau (u 3370 (58) ng·h/mL), time to steady state (6 days), and Tmax (1.5 (0.5, 6.5) hours).3
- Volume of distribution
The apparent volume of distribution [Mean (%CV)] of nirogacestat is 1430 (65) L.3
- Protein binding
Nirogacestat has a high level of serum protein binding of 99.6%, with 94.6% to serum albumin and 97.9% to alpha-1 acid glycoprotein.3
- Metabolism
Nirogacestat is expected to be metabolized primarily through the N-dealkylation via CYP3A4 (85%), with the involvement of CYP3A4, CYP2C19, CYP2C9, and CYP2D6 in a minor secondary pathway.3
- Route of elimination
Nirogacestat is excreted mostly in feces (38%) and urine 17%, with less than 1% of the unchanged drug remains in the urine. It can also be eliminated through expired air (9.7%).3
- Half-life
The terminal elimination half-life [Mean (%CV)] of nirogacestat is 23 (37) hr .3
- Clearance
The apparent systemic clearance [Mean (%CV)] of nirogacestat is 45 (58) L/hr.3
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Based on findings from animal studies and its mechanism of action, nirogacestat can cause fetal harm or loss of pregnancy when administered to a pregnant woman. Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity and embryo-fetal death at maternal exposures below the human exposure at the recommended dose of 150 mg twice daily. There are no available data on the use of nirogacestat in pregnant women. Advise pregnant women of the potential risk to a fetus.3
Due to the high level of protein binding, nirogacestat is not expected to be dialyzable.3
In a 6-month carcinogenicity study, transgenic rasH2 mice received up to 100 mg/kg/day of oral nirogacestat, resulting in mean exposure levels (AUC) less than those in humans at the recommended dose of 150 mg twice daily. No statistically significant neoplastic findings occurred. The carcinogenic potential of nirogacestat in rats has not been assessed.3
Nirogacestat was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro chromosome aberration assay in human lymphocytes or in vivo rat bone marrow micronucleus study.3
Nirogacestat resulted in reduced fertility when administered to male and female rats at doses ≥ 5 mg/kg/day (approximately 0.16 times the recommended dose of 150 mg twice daily based on body surface area (BSA), and a lack of fertility when administered to male and female rats at doses ≥ 40 mg/kg/day (approximately 1.3 times the recommended dose of 150 mg twice daily based on BSA). Adverse findings in rats included ovarian atrophy, reduced testes weights, and decreased sperm concentration and motility.3
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Nirogacestat can be increased when it is combined with Abametapir. Abatacept The metabolism of Nirogacestat can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Nirogacestat. Abiraterone The metabolism of Nirogacestat can be decreased when combined with Abiraterone. Abrocitinib The serum concentration of Nirogacestat can be increased when it is combined with Abrocitinib. - Food Interactions
- Avoid grapefruit products. Nirogacestat is a CYP3A substrate and grapefruit is a known CYP3A inhibitors.
- Take separate from antacids. take nirogacestat 2 hours before or 2 hours after taking the antacid.
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ogsiveo Tablet, film coated 100 mg/1 Oral SpringWorks Therapeutics, Inc. 2023-11-27 Not applicable US 
Ogsiveo Tablet, film coated 50 mg/1 Oral SpringWorks Therapeutics, Inc. 2023-11-27 Not applicable US Ogsiveo Tablet, film coated 150 mg/1 Oral SpringWorks Therapeutics, Inc. 2023-11-27 Not applicable US
Categories
- Drug Categories
- Amino Acids
- Amino Acids, Branched-Chain
- Amino Acids, Peptides, and Proteins
- Amyloid Precursor Protein Secretases, antagonists & inhibitors
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2B6 Inducers (strength unknown)
- Cytochrome P-450 CYP2C19 Inducers
- Cytochrome P-450 CYP2C19 Inducers (strength unknown)
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C8 Inducers
- Cytochrome P-450 CYP2C8 Inducers (strength unknown)
- Cytochrome P-450 CYP2C9 Inducers
- Cytochrome P-450 CYP2C9 Inducers (strength unknown)
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Substrates
- Enzyme Inhibitors
- Gamma Secretase Inhibitors and Modulators
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as alpha amino acid amides. These are amide derivatives of alpha amino acids.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Alpha amino acid amides
- Alternative Parents
- Tetralins / N-arylamides / Aralkylamines / N-substituted imidazoles / Imidolactams / Fatty amides / Aryl fluorides / Heteroaromatic compounds / Secondary carboxylic acid amides / Dialkylamines show 5 more
- Substituents
- Alpha-amino acid amide / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Carbonyl group show 21 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- QZ62892OFJ
- CAS number
- 1290543-63-3
- InChI Key
- VFCRKLWBYMDAED-REWPJTCUSA-N
- 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
- IUPAC Name
- (2S)-2-{[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]amino}-N-(1-{1-[(2,2-dimethylpropyl)amino]-2-methylpropan-2-yl}-1H-imidazol-4-yl)pentanamide
- SMILES
- CCC[C@H](N[C@H]1CCC2=CC(F)=CC(F)=C2C1)C(=O)NC1=CN(C=N1)C(C)(C)CNCC(C)(C)C
References
- General References
- Gounder M, Ratan R, Alcindor T, Schoffski P, van der Graaf WT, Wilky BA, Riedel RF, Lim A, Smith LM, Moody S, Attia S, Chawla S, D'Amato G, Federman N, Merriam P, Van Tine BA, Vincenzi B, Benson C, Bui NQ, Chugh R, Tinoco G, Charlson J, Dileo P, Hartner L, Lapeire L, Mazzeo F, Palmerini E, Reichardt P, Stacchiotti S, Bailey HH, Burgess MA, Cote GM, Davis LE, Deshpande H, Gelderblom H, Grignani G, Loggers E, Philip T, Pressey JG, Kummar S, Kasper B: Nirogacestat, a gamma-Secretase Inhibitor for Desmoid Tumors. N Engl J Med. 2023 Mar 9;388(10):898-912. doi: 10.1056/NEJMoa2210140. [Article]
- Shih IeM, Wang TL: Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res. 2007 Mar 1;67(5):1879-82. doi: 10.1158/0008-5472.CAN-06-3958. [Article]
- FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
- SpringWorks Therapeutics Announces FDA Approval of OGSIVEO™ (nirogacestat) as the First and Only Treatment for Adults with Desmoid Tumors [Link]
- External Links
- PubChem Compound
- 46224413
- PubChem Substance
- 347828323
- ChemSpider
- 26232306
- BindingDB
- 50458159
- 2670631
- ChEMBL
- CHEMBL1770916
- ZINC
- ZINC000038217837
- Wikipedia
- Nirogacestat
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data3 Active Not Recruiting Treatment Desmoid Tumor 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Desmoid Tumor / Recurrent Desmoid Fibromatosis / Unresectable Desmoid Fibromatosis 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Ovarian Cancer / Ovarian Granulosa Cell Tumor 1 somestatus stop reason just information to hide 2 Completed Treatment Desmoid Tumor 1 somestatus stop reason just information to hide 2 Not Yet Recruiting Treatment Tumor 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 100 mg/1 Tablet, film coated Oral 150 mg/1 Tablet, film coated Oral 50 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US11807611 No 2022-09-08 2042-09-08 US US11612588 No 2022-07-08 2042-07-08 US US10941118 No 2019-08-09 2039-08-09 US US10710966 No 2019-08-09 2039-08-09 US US7795447 No 2005-08-18 2025-08-18 US US7342118 No 2005-08-18 2025-08-18 US US11820748 No 2019-08-09 2039-08-09 US US10590087 No 2019-08-09 2039-08-09 US US7951958 No 2005-03-11 2025-03-11 US US11504354 No 2022-07-08 2042-07-08 US US11845732 No 2019-08-09 2039-08-09 US US11844780 No 2022-09-08 2042-09-08 US US11872211 No 2023-05-19 2043-05-19 US US11884635 No 2019-08-09 2039-08-09 US US11884634 No 2019-08-09 2039-08-09 US US11905255 No 2019-08-09 2039-08-09 US US11925620 No 2023-05-19 2043-05-19 US US11925619 No 2023-05-19 2043-05-19 US US11938116 No 2023-05-19 2043-05-19 US US11957662 No 2023-05-19 2043-05-19 US US11951096 No 2023-05-19 2043-05-19 US US12011435 No 2023-05-19 2043-05-19 US US12011434 No 2023-05-19 2043-05-19 US US12036207 No 2023-05-19 2043-05-19 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility 11.4 mg/mL https://springworkstx.com/wp-content/uploads/2023/11/OGSIVEO-US-Prescribing-Information-11.27.23.pdf pKa 5.77, 7.13 https://springworkstx.com/wp-content/uploads/2023/11/OGSIVEO-US-Prescribing-Information-11.27.23.pdf - Predicted Properties
Property Value Source Water Solubility 0.0104 mg/mL ALOGPS logP 3.9 ALOGPS logP 5.5 Chemaxon logS -4.7 ALOGPS pKa (Strongest Acidic) 11.48 Chemaxon pKa (Strongest Basic) 10.45 Chemaxon Physiological Charge 2 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 70.98 Å2 Chemaxon Rotatable Bond Count 11 Chemaxon Refractivity 138.14 m3·mol-1 Chemaxon Polarizability 54.49 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0007-0226900000-297e245b7e04329da6b5 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-00dr-0024900000-8686d16aacf04b51af17 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0udi-2327900000-05c84a5bcf14ad2a2499 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-000i-0062900000-8eb3ecdb77f12607e92a Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0cdi-5914200000-8587eb418bbeabd46860 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-08fs-0922100000-b8623db4d62485ebdd3e Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 210.7112 predictedDeepCCS 1.0 (2019) [M+H]+ 213.10677 predictedDeepCCS 1.0 (2019) [M+Na]+ 219.0193 predictedDeepCCS 1.0 (2019)
Targets
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Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:10206644, PubMed:10545183, PubMed:10593990, PubMed:10811883, PubMed:10899933, PubMed:12679784, PubMed:12740439, PubMed:15274632, PubMed:20460383, PubMed:25043039, PubMed:26280335, PubMed:28269784, PubMed:30598546, PubMed:30630874). Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (PubMed:10593990, PubMed:10811883, PubMed:10899933, PubMed:9738936). Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11953314). Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:11953314, PubMed:9738936). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis (PubMed:16959576, PubMed:25394380). Involved in the regulation of neurite outgrowth (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression (By similarity)
- Specific Function
- Aspartic endopeptidase activity, intramembrane cleaving
- Gene Name
- PSEN1
- Uniprot ID
- P49768
- Uniprot Name
- Presenilin-1
- Molecular Weight
- 52667.34 Da
References
- Bhattarai A, Devkota S, Bhattarai S, Wolfe MS, Miao Y: Mechanisms of gamma-Secretase Activation and Substrate Processing. ACS Cent Sci. 2020 Jun 24;6(6):969-983. doi: 10.1021/acscentsci.0c00296. Epub 2020 Jun 4. [Article]
- Wolfe MS: Structure and Function of the gamma-Secretase Complex. Biochemistry. 2019 Jul 9;58(27):2953-2966. doi: 10.1021/acs.biochem.9b00401. Epub 2019 Jun 25. [Article]
- McCaw TR, Inga E, Chen H, Jaskula-Sztul R, Dudeja V, Bibb JA, Ren B, Rose JB: Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance. Oncologist. 2021 Apr;26(4):e608-e621. doi: 10.1002/onco.13627. Epub 2021 Jan 2. [Article]
- FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Modulator
- General Function
- Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12522139, PubMed:12679784, PubMed:12740439, PubMed:12763021, PubMed:24941111, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12679784, PubMed:12740439, PubMed:12763021, PubMed:24941111)
- Specific Function
- Endopeptidase activator activity
- Gene Name
- PSENEN
- Uniprot ID
- Q9NZ42
- Uniprot Name
- Gamma-secretase subunit PEN-2
- Molecular Weight
- 12029.01 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Modulator
- General Function
- Non-catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12297508, PubMed:12522139, PubMed:12679784, PubMed:12763021, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Required for normal gamma-secretase assembly (PubMed:12471034, PubMed:12522139, PubMed:12763021, PubMed:19369254). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable)
- Specific Function
- Endopeptidase activator activity
- Gene Name
- APH1A
- Uniprot ID
- Q96BI3
- Uniprot Name
- Gamma-secretase subunit APH-1A
- Molecular Weight
- 28995.7 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. May function in the cytoplasmic partitioning of proteins. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is involved in calcium homeostasis (PubMed:16959576). Is a regulator of mitochondrion-endoplasmic reticulum membrane tethering and modulates calcium ions shuttling between ER and mitochondria (PubMed:21285369)
- Specific Function
- Aspartic endopeptidase activity, intramembrane cleaving
- Gene Name
- PSEN2
- Uniprot ID
- P49810
- Uniprot Name
- Presenilin-2
- Molecular Weight
- 50139.905 Da
References
- Bhattarai A, Devkota S, Bhattarai S, Wolfe MS, Miao Y: Mechanisms of gamma-Secretase Activation and Substrate Processing. ACS Cent Sci. 2020 Jun 24;6(6):969-983. doi: 10.1021/acscentsci.0c00296. Epub 2020 Jun 4. [Article]
- Wolfe MS: Structure and Function of the gamma-Secretase Complex. Biochemistry. 2019 Jul 9;58(27):2953-2966. doi: 10.1021/acs.biochem.9b00401. Epub 2019 Jun 25. [Article]
- McCaw TR, Inga E, Chen H, Jaskula-Sztul R, Dudeja V, Bibb JA, Ren B, Rose JB: Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance. Oncologist. 2021 Apr;26(4):e608-e621. doi: 10.1002/onco.13627. Epub 2021 Jan 2. [Article]
- FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)
- Specific Function
- Anandamide 11,12 epoxidase activity
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
- Specific Function
- Anandamide 11,12 epoxidase activity
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
- Specific Function
- (r)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
- Specific Function
- (r)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55944.565 Da
References
- FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- Arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- Antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Functions as a transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
- Specific Function
- Not Available
Components:
References
- FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- Abc-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
Drug created at October 20, 2016 21:10 / Updated at August 26, 2024 19:23