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Identification
- Generic Name
- Rocaglamide
- DrugBank Accession Number
- DB15495
- Background
Rocaglamide, also referred to as rocaglamide-A, is the eponymous member of a class of anti-cancer phytochemicals known as rocaglamides.1 Rocaglamides are secondary metabolites of the plant genus Aglaia, and extracts of the plant have traditionally been used as a form of insect repellant due to its natural insecticidal properties.9 Reports of Aglaia anti-tumor activity date back as far as 1973, and rocaglamide-A was first isolated in 1982 from the species A. elliptifolia.1 Rocaglamide and a number of its derivatives (e.g. didesmethylrocaglamide) are currently being studied for use as chemotherapeutic agents in the treatment of various leukemias, lymphomas, and carcinomas, as well as adjuvant therapy in the treatment of certain chemotherapy-resistant cancers.7,8,10,3
- Type
- Small Molecule
- Groups
- Experimental
- Structure
Structure for Rocaglamide (DB15495)
- Weight
- Average: 505.567
Monoisotopic: 505.210052342 - Chemical Formula
- C29H31NO7
- Synonyms
- Not Available
Pharmacology
- Indication
Not Available
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Not Available
- Mechanism of action
Rocaglamide’s anti-tumor activity is driven primarily via inhibition of protein synthesis in tumor cells.1 Inhibition of protein synthesis is accomplished via inhibition of prohibitin 1 (PHB1) and prohibitin 2 (PHB2)2 - these proteins are necessary in the proliferation of cancer cells and are implicated in the Ras-mediated CRaf-MEK-ERK signaling pathway responsible for phosphorylating eIF4E, a key factor in the initiation of protein synthesis.2,1 The rocaglamide derivative silvestrol has also been observed to act directly on eIF4A, another translation initiation factor of the eIF4F complex ultimately responsible for initiation of protein synthesis.3
Inhibition of protein synthesis has a number of downstream effects. Many of the proteins that are down-regulated in response to protein synthesis inhibition in tumor cells are short-lived proteins responsible for regulation of the cell cycle, such as Cdc25A.1 Cdc25A is an oncogene that can become overexpressed in certain cancers and lead to unchecked cell growth.4 In addition to inhibiting its synthesis via the mechanism described above, rocaglamide promotes degradation of Cdc25A via activation of the ATM/ATR-Chk1/Chk2 checkpoint pathway5. This pathway is normally activated in response to DNA damage and serves to reduce the expression of proteins responsible for cell cycle progression, thereby inhibiting proliferation of damaged (i.e. tumour) cells. Rocaglamide’s inhibition of protein synthesis also appears to prevent the actions of the transcription factor heat shock factor 1 (HSF1), leading to an increased expression of thioredoxin-interacting protein (TXNIP) which is negatively regulated by HSF1.6 TXNIP is a negative regulator of cell glucose uptake, and its increased expression blocks glucose uptake and consequently impairs the proliferation of malignant cells.6
Rocaglamide also appears to induce apoptosis in tumor cells via activation of the pro-apoptotic proteins p38 and JNK and inhibition of the anti-apoptotic Mcl-1 protein.1 Similarly, it has been studied as an adjuvant in TRAIL-resistant cancers due to its ability to inhibit the synthesis of c-FLIP and IAP/XIAP - these anti-apoptotic proteins can become elevated in certain cancers, preventing the induction of apoptosis and resulting in resistance to TRAIL-based therapies.7,8
Target Actions Organism AProhibitin 1 inhibitorHumans ATranscription factor RelB inhibitorHumans ANuclear factor NF-kappa-B p100 subunit inhibitorHumans ATranscription factor p65 inhibitorHumans AProto-oncogene c-Rel inhibitorHumans ANuclear factor NF-kappa-B p105 subunit inhibitorHumans AProhibitin-2 inhibitorHumans - Absorption
Not Available
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
- Not Available
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
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Not Available
- 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.Not Available
- Food Interactions
- Not Available
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as flavaglines. These are heterocyclic compounds with a structure characterized by a cyclopenta[b]benzofuran skeleton.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Benzofurans
- Sub Class
- Flavaglines
- Direct Parent
- Flavaglines
- Alternative Parents
- Stilbenes / Coumarans / Anisoles / Methoxybenzenes / Phenoxy compounds / Alkyl aryl ethers / Tertiary carboxylic acid amides / Tertiary alcohols / Cyclic alcohols and derivatives / 1,2-diols show 7 more
- Substituents
- 1,2-diol / Alcohol / Alkyl aryl ether / Anisole / Aromatic heteropolycyclic compound / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Coumaran show 19 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- monocarboxylic acid amide, organic heterotricyclic compound, monomethoxybenzene (CHEBI:66309)
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- FRG4N852F7
- CAS number
- 84573-16-0
- InChI Key
- DAPAQENNNINUPW-IDAMAFBJSA-N
- InChI
- InChI=1S/C29H31NO7/c1-30(2)27(32)23-24(17-9-7-6-8-10-17)29(18-11-13-19(34-3)14-12-18)28(33,26(23)31)25-21(36-5)15-20(35-4)16-22(25)37-29/h6-16,23-24,26,31,33H,1-5H3/t23-,24-,26-,28+,29+/m1/s1
- IUPAC Name
- (2S,3R,4R,5S,6R)-2,3-dihydroxy-10,12-dimethoxy-6-(4-methoxyphenyl)-N,N-dimethyl-5-phenyl-7-oxatricyclo[6.4.0.0^{2,6}]dodeca-1(8),9,11-triene-4-carboxamide
- SMILES
- COC1=CC=C(C=C1)[C@@]12OC3=C(C(OC)=CC(OC)=C3)[C@]1(O)[C@H](O)[C@@H]([C@H]2C1=CC=CC=C1)C(=O)N(C)C
References
- General References
- Li-Weber M: Molecular mechanisms and anti-cancer aspects of the medicinal phytochemicals rocaglamides (=flavaglines). Int J Cancer. 2015 Oct 15;137(8):1791-9. doi: 10.1002/ijc.29013. Epub 2014 Jun 11. [Article]
- Polier G, Neumann J, Thuaud F, Ribeiro N, Gelhaus C, Schmidt H, Giaisi M, Kohler R, Muller WW, Proksch P, Leippe M, Janssen O, Desaubry L, Krammer PH, Li-Weber M: The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2. Chem Biol. 2012 Sep 21;19(9):1093-104. doi: 10.1016/j.chembiol.2012.07.012. [Article]
- Cencic R, Carrier M, Galicia-Vazquez G, Bordeleau ME, Sukarieh R, Bourdeau A, Brem B, Teodoro JG, Greger H, Tremblay ML, Porco JA Jr, Pelletier J: Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol. PLoS One. 2009;4(4):e5223. doi: 10.1371/journal.pone.0005223. Epub 2009 Apr 29. [Article]
- Kristjansdottir K, Rudolph J: Cdc25 phosphatases and cancer. Chem Biol. 2004 Aug;11(8):1043-51. doi: 10.1016/j.chembiol.2004.07.007. [Article]
- Neumann J, Boerries M, Kohler R, Giaisi M, Krammer PH, Busch H, Li-Weber M: The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints. Int J Cancer. 2014 Apr 15;134(8):1991-2002. doi: 10.1002/ijc.28521. Epub 2013 Oct 21. [Article]
- Santagata S, Mendillo ML, Tang YC, Subramanian A, Perley CC, Roche SP, Wong B, Narayan R, Kwon H, Koeva M, Amon A, Golub TR, Porco JA Jr, Whitesell L, Lindquist S: Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science. 2013 Jul 19;341(6143):1238303. doi: 10.1126/science.1238303. [Article]
- Zhu JY, Giaisi M, Kohler R, Muller WW, Muhleisen A, Proksch P, Krammer PH, Li-Weber M: Rocaglamide sensitizes leukemic T cells to activation-induced cell death by differential regulation of CD95L and c-FLIP expression. Cell Death Differ. 2009 Sep;16(9):1289-99. doi: 10.1038/cdd.2009.42. Epub 2009 Apr 17. [Article]
- Giaisi M, Kohler R, Fulda S, Krammer PH, Li-Weber M: Rocaglamide and a XIAP inhibitor cooperatively sensitize TRAIL-mediated apoptosis in Hodgkin's lymphomas. Int J Cancer. 2012 Aug 15;131(4):1003-8. doi: 10.1002/ijc.26458. Epub 2011 Nov 8. [Article]
- Schneider C, Bohnenstengel FI, Nugroho BW, Wray V, Witte L, Hung PD, Kiet LC, Proksch P: Insecticidal rocaglamide derivatives from Aglaia spectabilis (Meliaceae). Phytochemistry. 2000 Aug;54(8):731-6. doi: 10.1016/s0031-9422(00)00205-3. [Article]
- Hausott B, Greger H, Marian B: Flavaglines: a group of efficient growth inhibitors block cell cycle progression and induce apoptosis in colorectal cancer cells. Int J Cancer. 2004 May 10;109(6):933-40. doi: 10.1002/ijc.20033. [Article]
- External Links
- ChemSpider
- 293974
- BindingDB
- 50196926
- ChEBI
- 66309
- ChEMBL
- CHEMBL438139
- ZINC
- ZINC000005664046
- PDBe Ligand
- RCG
- Wikipedia
- Rocaglamide
- PDB Entries
- 5zc9
Clinical Trials
- Clinical Trials
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Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0176 mg/mL ALOGPS logP 3.53 ALOGPS logP 2.39 Chemaxon logS -4.5 ALOGPS pKa (Strongest Acidic) 11.63 Chemaxon pKa (Strongest Basic) -1.7 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 7 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 97.69 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 136.26 m3·mol-1 Chemaxon Polarizability 53.71 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 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
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 236.0555399 predictedDarkChem Lite v0.1.0 [M+H]+ 236.3195399 predictedDarkChem Lite v0.1.0 [M+Na]+ 235.6035399 predictedDarkChem Lite v0.1.0
Targets
Build, predict & validate machine-learning models
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
- Protein with pleiotropic attributes mediated in a cell-compartment- and tissue-specific manner, which include the plasma membrane-associated cell signaling functions, mitochondrial chaperone, and transcriptional co-regulator of transcription factors in the nucleus (PubMed:11302691, PubMed:20959514, PubMed:28017329, PubMed:31522117). Plays a role in adipose tissue and glucose homeostasis in a sex-specific manner (By similarity). Contributes to pulmonary vascular remodeling by accelerating proliferation of pulmonary arterial smooth muscle cells (By similarity)
- Specific Function
- complement component C3a binding
- Gene Name
- PHB1
- Uniprot ID
- P35232
- Uniprot Name
- Prohibitin 1
- Molecular Weight
- 29803.775 Da
References
- Li-Weber M: Molecular mechanisms and anti-cancer aspects of the medicinal phytochemicals rocaglamides (=flavaglines). Int J Cancer. 2015 Oct 15;137(8):1791-9. doi: 10.1002/ijc.29013. Epub 2014 Jun 11. [Article]
- Polier G, Neumann J, Thuaud F, Ribeiro N, Gelhaus C, Schmidt H, Giaisi M, Kohler R, Muller WW, Proksch P, Leippe M, Janssen O, Desaubry L, Krammer PH, Li-Weber M: The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2. Chem Biol. 2012 Sep 21;19(9):1093-104. doi: 10.1016/j.chembiol.2012.07.012. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric RelB-p50 and RelB-p52 complexes are transcriptional activators. RELB neither associates with DNA nor with RELA/p65 or REL. Stimulates promoter activity in the presence of NFKB2/p49. As a member of the NUPR1/RELB/IER3 survival pathway, may provide pancreatic ductal adenocarcinoma with remarkable resistance to cell stress, such as starvation or gemcitabine treatment. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer in a CRY1/CRY2 independent manner. Increased repression of the heterodimer is seen in the presence of NFKB2/p52. Is required for both T and B lymphocyte maturation and function (PubMed:26385063)
- Specific Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- Gene Name
- RELB
- Uniprot ID
- Q01201
- Uniprot Name
- Transcription factor RelB
- Molecular Weight
- 62133.86 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
- NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. In a non-canonical activation pathway, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. The NF-kappa-B heterodimeric RelB-p52 complex is a transcriptional activator. The NF-kappa-B p52-p52 homodimer is a transcriptional repressor. NFKB2 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p100 and generation of p52 by a cotranslational processing. The proteasome-mediated process ensures the production of both p52 and p100 and preserves their independent function. p52 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. p52 and p100 are respectively the minor and major form; the processing of p100 being relatively poor. Isoform p49 is a subunit of the NF-kappa-B protein complex, which stimulates the HIV enhancer in synergy with p65. In concert with RELB, regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer
- Specific Function
- DNA-binding transcription activator activity, RNA polymerase II-specific
- Gene Name
- NFKB2
- Uniprot ID
- Q00653
- Uniprot Name
- Nuclear factor NF-kappa-B p100 subunit
- Molecular Weight
- 96748.355 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
- NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The heterodimeric RELA-NFKB1 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. The NF-kappa-B heterodimeric RELA-NFKB1 and RELA-REL complexes, for instance, function as transcriptional activators. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. The inhibitory effect of I-kappa-B on NF-kappa-B through retention in the cytoplasm is exerted primarily through the interaction with RELA. RELA shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Beside its activity as a direct transcriptional activator, it is also able to modulate promoters accessibility to transcription factors and thereby indirectly regulate gene expression. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Essential for cytokine gene expression in T-cells (PubMed:15790681). The NF-kappa-B homodimeric RELA-RELA complex appears to be involved in invasin-mediated activation of IL-8 expression. Key transcription factor regulating the IFN response during SARS-CoV-2 infection (PubMed:33440148)
- Specific Function
- actinin binding
- Gene Name
- RELA
- Uniprot ID
- Q04206
- Uniprot Name
- Transcription factor p65
- Molecular Weight
- 60218.53 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
- Proto-oncogene that may play a role in differentiation and lymphopoiesis. NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. The NF-kappa-B heterodimer RELA/p65-c-Rel is a transcriptional activator
- Specific Function
- DNA-binding transcription activator activity, RNA polymerase II-specific
- Gene Name
- REL
- Uniprot ID
- Q04864
- Uniprot Name
- Proto-oncogene c-Rel
- Molecular Weight
- 68519.05 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
- NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105
- Specific Function
- actinin binding
- Gene Name
- NFKB1
- Uniprot ID
- P19838
- Uniprot Name
- Nuclear factor NF-kappa-B p105 subunit
- Molecular Weight
- 105355.175 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
- Protein with pleiotropic attributes mediated in a cell-compartment- and tissue-specific manner, which include the plasma membrane-associated cell signaling functions, mitochondrial chaperone, and transcriptional co-regulator of transcription factors and sex steroid hormones in the nucleus
- Specific Function
- amide binding
- Gene Name
- PHB2
- Uniprot ID
- Q99623
- Uniprot Name
- Prohibitin-2
- Molecular Weight
- 33296.06 Da
References
- Li-Weber M: Molecular mechanisms and anti-cancer aspects of the medicinal phytochemicals rocaglamides (=flavaglines). Int J Cancer. 2015 Oct 15;137(8):1791-9. doi: 10.1002/ijc.29013. Epub 2014 Jun 11. [Article]
- Polier G, Neumann J, Thuaud F, Ribeiro N, Gelhaus C, Schmidt H, Giaisi M, Kohler R, Muller WW, Proksch P, Leippe M, Janssen O, Desaubry L, Krammer PH, Li-Weber M: The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2. Chem Biol. 2012 Sep 21;19(9):1093-104. doi: 10.1016/j.chembiol.2012.07.012. [Article]
Drug created at September 26, 2019 16:14 / Updated at October 03, 2024 04:25