Explore a selection of our essential drug information below, or:
Identification
- Generic Name
- Alvespimycin
- DrugBank Accession Number
- DB12442
- Background
Alvespimycin is a derivative of geldanamycin and heat shock protein (HSP) 90 inhibitor. It has been used in trials studying the treatment of solid tumor in various cancer as an antitumor agent. In comparison to the first HSP90 inhibitor tanespimycin, it exhibits some pharmacologically desirable properties such as reduced metabolic liability, lower plasma protein binding, increased water solubility, higher oral bioavailability, reduced hepatotoxicity and superior antitumor activity 1.
- Type
- Small Molecule
- Groups
- Investigational
- Structure
Structure for Alvespimycin (DB12442)
- Weight
- Average: 616.7455
Monoisotopic: 616.347214532 - Chemical Formula
- C32H48N4O8
- Synonyms
- 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
- 17-DMAG
- Alvespimycin
- DMAG
- External IDs
- KOS 1022
- KOS-1022
- KOS1022
- NSC-707545
Pharmacology
- Indication
Investigated for use as an antineoplastic agent for solid tumors, advanced solid tumours or acute myeloid leukaemia.
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Alvespimycin mediates an antitumor activity through HSP90 inhibition that targets client proteins for proteasomal destruction, including oncogenic kinases such as BRAF. The administration of the drug is shown to result in the depletion of client proteins that have oncogenic activity and potential induction of HSP70 (HSP72) 1. It is more selective for tumors over normal tissue. A study also reports that alvespimycin enhances the potency of telomerase inhibition by imetelstat in pre-clinical models of human osteosarcoma 3.
- Mechanism of action
Alvespimycin inhibits HSP90 and its regulation of correct folding and function of many cellular signalling proteins, which are referred to as Hsp90 client proteins. These client proteins are also referred to as oncoproteins and include Her-2, EGFR, Akt, Raf-1, p53, Bcr-Abl, Cdk4, Cdk6 and steroid receptors that are involved in cellular signalling pathways that drive cellular proliferation and counteract apoptosis. They are often over-expressed or mutated in tumors, and contribute to cancer progression and therapy resistance 2. Alvespimycin promotes an anticancer activity by disrupting Hsp90's chaperone function and inducing the proteasomal degradation of oncoproteins. It is shown to reduce the levels of CDK4 and ERBB2 1.
Target Actions Organism AHeat shock protein HSP 90-alpha inhibitorHumans - Absorption
Increasing concentration of the drug results in dose-proportional increase in the plasma concentration. At the maximum tolerated dose of 80mg/m^2, the plasma concentration exceeded 63nM (mean IC50 for 17-DMAG in the NCI 60 human tumor cell line panel) for less than 24 hours in all patients. The mean peak concentration (Cmax) reached 2680 nmol/L at this dose.
- Volume of distribution
At the maximum tolerated dose of 80mg/m^2, the mean Vd value is 385 L.
- Protein binding
Reported to be minimal.
- Metabolism
Alvespimycin demonstrates redox cycling catalyzed by purified human cytochrome P450 reductase (CYP3A4/3A5) to quinones and hydroquinones. It could also form glutathione conjugates at the 19-position on the quinone ring 6. However in vivo and in vitro studies suggest that weak metabolism of alvespimysin occurs in humans.
- Route of elimination
Mainly renal and biliary elimination pathways. In a mice study, the excreted urine 24 hours post-dose recovered 10.6–14.8% of delivered dose unchanged 2.
- Half-life
The half-life across all dose levels ranged from 9.9 to 54.1 h (median, 18.2 h) 5.
- Clearance
The mean clearance is 18.9 L/hr at the dose of 80mg/m^2.
- Adverse Effects
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Alvespimycin exhibits a dose-limiting toxicity where most toxic effects were experienced at ≥ 80mg/m^2 in Phase I clinical trials. Common adverse effects include nausea, vomiting, fatigue, hematologic toxicity, liver enzyme disturbances and ocular disturbances including blurred vision and keratitis. They are reported to be generally reversible. The doses lower than 80mg/m^2 are well-tolerated. The dose-limiting
- 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
Products
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Ingredient UNII CAS InChI Key Alvespimycin hydrochloride 612K359T69 467214-21-7 DFSYBWLNYPEFJK-IHLRWNDRSA-N
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as macrolactams. These are cyclic amides of amino carboxylic acids, having a 1-azacycloalkan-2-one structure, or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. They are nitrogen analogues (the a nitrogen atom replacing the o atom of the cyclic carboxylic acid group ) of the naturally occurring macrolides.
- Kingdom
- Organic compounds
- Super Class
- Phenylpropanoids and polyketides
- Class
- Macrolactams
- Sub Class
- Not Available
- Direct Parent
- Macrolactams
- Alternative Parents
- Vinylogous amides / Carbamate esters / Trialkylamines / Secondary carboxylic acid amides / Secondary alcohols / Organic carbonic acids and derivatives / Lactams / Cyclic ketones / Enamines / Dialkylamines show 5 more
- Substituents
- Alcohol / Aliphatic heteropolycyclic compound / Amine / Amino acid or derivatives / Azacycle / Carbamic acid ester / Carbonic acid derivative / Carbonyl group / Carboxamide group / Carboxylic acid derivative show 22 more
- Molecular Framework
- Aliphatic heteropolycyclic compounds
- External Descriptors
- tertiary amino compound, secondary amino compound, lactam, macrocycle, benzoquinones (CHEBI:65324)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 001L2FE0M3
- CAS number
- 467214-20-6
- InChI Key
- KUFRQPKVAWMTJO-LMZWQJSESA-N
- InChI
- InChI=1S/C32H48N4O8/c1-18-14-22-27(34-12-13-36(5)6)24(37)17-23(29(22)39)35-31(40)19(2)10-9-11-25(42-7)30(44-32(33)41)21(4)16-20(3)28(38)26(15-18)43-8/h9-11,16-18,20,25-26,28,30,34,38H,12-15H2,1-8H3,(H2,33,41)(H,35,40)/b11-9-,19-10+,21-16+/t18-,20+,25+,26+,28-,30+/m1/s1
- IUPAC Name
- (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-{[2-(dimethylamino)ethyl]amino}-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate
- SMILES
- CO[C@H]1C[C@H](C)CC2=C(NCCN(C)C)C(=O)C=C(NC(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@H]1O)C2=O
References
- General References
- Pacey S, Wilson RH, Walton M, Eatock MM, Hardcastle A, Zetterlund A, Arkenau HT, Moreno-Farre J, Banerji U, Roels B, Peachey H, Aherne W, de Bono JS, Raynaud F, Workman P, Judson I: A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors. Clin Cancer Res. 2011 Mar 15;17(6):1561-70. doi: 10.1158/1078-0432.CCR-10-1927. Epub 2011 Jan 28. [Article]
- Hu ZY, Lu J, Zhao Y: A physiologically based pharmacokinetic model of alvespimycin in mice and extrapolation to rats and humans. Br J Pharmacol. 2014 Jun;171(11):2778-89. doi: 10.1111/bph.12609. [Article]
- Hu Y, Bobb D, He J, Hill DA, Dome JS: The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma. Cancer Biol Ther. 2015;16(6):949-57. doi: 10.1080/15384047.2015.1040964. Epub 2015 Apr 28. [Article]
- Bae J, Munshi A, Li C, Samur M, Prabhala R, Mitsiades C, Anderson KC, Munshi NC: Heat shock protein 90 is critical for regulation of phenotype and functional activity of human T lymphocytes and NK cells. J Immunol. 2013 Feb 1;190(3):1360-71. doi: 10.4049/jimmunol.1200593. Epub 2013 Jan 4. [Article]
- Kummar S, Gutierrez ME, Gardner ER, Chen X, Figg WD, Zajac-Kaye M, Chen M, Steinberg SM, Muir CA, Yancey MA, Horneffer YR, Juwara L, Melillo G, Ivy SP, Merino M, Neckers L, Steeg PS, Conley BA, Giaccone G, Doroshow JH, Murgo AJ: Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies. Eur J Cancer. 2010 Jan;46(2):340-7. doi: 10.1016/j.ejca.2009.10.026. Epub 2009 Nov 27. [Article]
- Guo W, Reigan P, Siegel D, Ross D: Enzymatic reduction and glutathione conjugation of benzoquinone ansamycin heat shock protein 90 inhibitors: relevance for toxicity and mechanism of action. Drug Metab Dispos. 2008 Oct;36(10):2050-7. doi: 10.1124/dmd.108.022004. Epub 2008 Jul 17. [Article]
- External Links
- PubChem Compound
- 5288674
- PubChem Substance
- 347828683
- ChemSpider
- 16744073
- BindingDB
- 50005781
- ChEBI
- 65324
- ChEMBL
- CHEMBL383824
- ZINC
- ZINC000100030312
- PDBe Ligand
- KOS
- Wikipedia
- 17-Dimethylaminoethylamino-17-demethoxygeldanamycin
- PDB Entries
- 1osf
- MSDS
- Download (24.3 KB)
Clinical Trials
- Clinical Trials
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Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Soluble A19243 - Predicted Properties
Property Value Source Water Solubility 0.0211 mg/mL ALOGPS logP 1.84 ALOGPS logP 1.85 Chemaxon logS -4.5 ALOGPS pKa (Strongest Acidic) 12.78 Chemaxon pKa (Strongest Basic) 8.56 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 9 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 169.52 Å2 Chemaxon Rotatable Bond Count 8 Chemaxon Refractivity 172.38 m3·mol-1 Chemaxon Polarizability 66.39 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No 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]- 240.85155 predictedDeepCCS 1.0 (2019) [M+H]+ 242.57527 predictedDeepCCS 1.0 (2019) [M+Na]+ 248.90424 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity which is essential for its chaperone activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function (PubMed:11274138, PubMed:12526792, PubMed:15577939, PubMed:15937123, PubMed:27353360, PubMed:29127155). Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself (PubMed:29127155). Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone. After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle (PubMed:26991466, PubMed:27295069). Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70 (PubMed:12526792). Apart from its chaperone activity, it also plays a role in the regulation of the transcription machinery. HSP90 and its co-chaperones modulate transcription at least at three different levels (PubMed:25973397). In the first place, they alter the steady-state levels of certain transcription factors in response to various physiological cues (PubMed:25973397). Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment (PubMed:25973397). Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression (PubMed:25973397). Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205). Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation (PubMed:24613385). Mediates the association of TOMM70 with IRF3 or TBK1 in mitochondrial outer membrane which promotes host antiviral response (PubMed:20628368, PubMed:25609812)
- Specific Function
- Atp binding
- Gene Name
- HSP90AA1
- Uniprot ID
- P07900
- Uniprot Name
- Heat shock protein HSP 90-alpha
- Molecular Weight
- 84659.015 Da
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
- Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
- Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [Article]
- 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]
Drug created at October 20, 2016 22:24 / Updated at February 21, 2021 18:53