Identification

Name
Alvespimycin
Accession Number
DB12442
Type
Small Molecule
Groups
Investigational
Description

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].

Structure
Thumb
Synonyms
  • 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
  • 17-DMAG
External IDs
NSC-707545
Product Ingredients
IngredientUNIICASInChI Key
Alvespimycin hydrochloride612K359T69467214-21-7DFSYBWLNYPEFJK-IHLRWNDRSA-N
Categories
UNII
001L2FE0M3
CAS number
467214-20-6
Weight
Average: 616.7455
Monoisotopic: 616.347214532
Chemical Formula
C32H48N4O8
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}-3,13-dihydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-20,22-dioxo-2-azabicyclo[16.3.1]docosa-1(21),2,4,6,10,18-hexaen-9-yl]oxy}methanimidic acid
SMILES
[H]/C1=C([H])/[[email protected]]([H])(OC)[[email protected]@]([H])(OC(O)=N)\C(C)=C([H])\[[email protected]]([H])(C)[[email protected]@]([H])(O)[[email protected]]([H])(C[[email protected]]([H])(C)CC2=C(NCCN(C)C)C(=O)C=C(N=C(O)\C(C)=C\1/[H])C2=O)OC

Pharmacology

Indication

Investigated for use as an antineoplastic agent for solid tumors, advanced solid tumours or acute myeloid leukaemia.

Structured Indications
Not Available
Pharmacodynamics

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].

TargetActionsOrganism
AHeat shock protein HSP 90-alpha
inhibitor
Human
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.

Toxicity

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

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:21278242]
  2. 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. [PubMed:24471734]
  3. 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. [PubMed:25920748]
  4. 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. [PubMed:23293352]
  5. 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. [PubMed:19945858]
  6. 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. [PubMed:18635747]
External Links
PubChem Compound
5288674
PubChem Substance
347828683
ChemSpider
16744073
BindingDB
50005781
ChEBI
65324
ChEMBL
CHEMBL383824
HET
KOS
Wikipedia
17-Dimethylaminoethylamino-17-demethoxygeldanamycin
PDB Entries
1osf
MSDS
Download (24.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAnaplastic Large Cell Lymphoma / Angioimmunoblastic T-Cell Lymphoma / Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue / Intraocular Lymphoma / Nodal marginal zone B-cell lymphomas / Recurrent Adult Burkitt Lymphoma / Recurrent Adult Diffuse Large Cell Lymphoma / Recurrent Adult Diffuse Mixed Cell Lymphoma / Recurrent Adult Diffuse Small Cleaved Cell Lymphoma / Recurrent Adult Hodgkin's Lymphoma / Recurrent Adult T-Cell Leukemia/Lymphoma / Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma / Recurrent Grade 1 Follicular Lymphoma / Recurrent Grade 2 Follicular Lymphoma / Recurrent Grade 3 Follicular Lymphoma / Recurrent Mantle Cell Lymphoma / Recurrent Marginal Zone Lymphoma / Recurrent Mycosis Fungoides/Sezary Syndrome / Recurrent Small Lymphocytic Lymphoma / Splenic Marginal Zone Lymphoma / Stage III Adult Burkitt Lymphoma / Stage III Adult Diffuse Large Cell Lymphoma / Stage III Adult Diffuse Mixed Cell Lymphoma / Stage III Adult Diffuse Small Cleaved Cell Lymphoma / Stage III Adult Hodgkin Lymphoma / Stage III Adult T-Cell Leukemia/Lymphoma / Stage III Cutaneous T-Cell Non-Hodgkin Lymphoma / Stage III Grade 1 Follicular Lymphoma / Stage III Grade 2 Follicular Lymphoma / Stage III Grade 3 Follicular Lymphoma / Stage III Mantle Cell Lymphoma / Stage III Marginal Zone Lymphoma / Stage III Mycosis Fungoides/Sezary Syndrome / Stage III Small Lymphocytic Lymphoma / Stage IV Adult Burkitt Lymphoma / Stage IV Adult Diffuse Large Cell Lymphoma / Stage IV Adult Diffuse Mixed Cell Lymphoma / Stage IV Adult Diffuse Small Cleaved Cell Lymphoma / Stage IV Adult Hodgkin Lymphoma / Stage IV Adult T-Cell Leukemia/Lymphoma / Stage IV Cutaneous T-Cell Non-Hodgkin Lymphoma / Stage IV Grade 1 Follicular Lymphoma / Stage IV Grade 2 Follicular Lymphoma / Stage IV Grade 3 Follicular Lymphoma / Stage IV Mantle Cell Lymphoma / Stage IV Marginal Zone Lymphoma / Stage IV Mycosis Fungoides/Sezary Syndrome / Stage IV Small Lymphocytic Lymphoma / Unspecified Adult Solid Tumor, Protocol Specific / Waldenstrom's Macroglobulinemia (WM)1
1CompletedTreatmentCancer, Breast / Tumors, Solid1
1CompletedTreatmentMale Breast Cancer / Recurrent Adenoid Cystic Carcinoma of the Oral Cavity / Recurrent Basal Cell Carcinoma of the Lip / Recurrent Breast Cancer / Recurrent Colon Cancer / Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity / Recurrent Gastric Cancer / Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity / Recurrent Lymphoepithelioma of the Nasopharynx / Recurrent Lymphoepithelioma of the Oropharynx / Recurrent Melanoma / Recurrent Metastatic Squamous Neck Cancer With Occult Primary / Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity / Recurrent Mucoepidermoid Carcinoma of the Oral Cavity / Recurrent Ovarian Epithelial Cancer / Recurrent Prostate Cancer / Recurrent Renal Cell Cancer / Recurrent Salivary Gland Cancer / Recurrent Squamous Cell Carcinoma of the Hypopharynx / Recurrent Squamous Cell Carcinoma of the Larynx / Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity / Recurrent Squamous Cell Carcinoma of the Nasopharynx / Recurrent Squamous Cell Carcinoma of the Oropharynx / Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity / Recurrent Verrucous Carcinoma of the Larynx / Recurrent Verrucous Carcinoma of the Oral Cavity / Stage III Adenoid Cystic Carcinoma of the Oral Cavity / Stage III Basal Cell Carcinoma of the Lip / Stage III Colon Cancer / Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity / Stage III Gastric Cancer / Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity / Stage III Lymphoepithelioma of the Nasopharynx / Stage III Lymphoepithelioma of the Oropharynx / Stage III Melanoma / Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity / Stage III Mucoepidermoid Carcinoma of the Oral Cavity / Stage III Ovarian Epithelial Cancer / Stage III Renal Cell Cancer / Stage III Salivary Gland Cancer / Stage III Squamous Cell Carcinoma of the Hypopharynx / Stage III Squamous Cell Carcinoma of the Larynx / Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity / Stage III Squamous Cell Carcinoma of the Nasopharynx / Stage III Squamous Cell Carcinoma of the Oropharynx / Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity / Stage III Verrucous Carcinoma of the Larynx / Stage III Verrucous Carcinoma of the Oral Cavity / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer / Stage IV Adenoid Cystic Carcinoma of the Oral Cavity / Stage IV Basal Cell Carcinoma of the Lip / Stage IV Breast Cancer / Stage IV Colon Cancer / Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity / Stage IV Gastric Cancer / Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity / Stage IV Lymphoepithelioma of the Nasopharynx / Stage IV Lymphoepithelioma of the Oropharynx / Stage IV Melanoma / Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity / Stage IV Mucoepidermoid Carcinoma of the Oral Cavity / Stage IV Ovarian Epithelial Cancer / Stage IV Prostate Cancer / Stage IV Renal Cell Cancer / Stage IV Salivary Gland Cancer / Stage IV Squamous Cell Carcinoma of the Hypopharynx / Stage IV Squamous Cell Carcinoma of the Larynx / Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity / Stage IV Squamous Cell Carcinoma of the Nasopharynx / Stage IV Squamous Cell Carcinoma of the Oropharynx / Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity / Stage IV Verrucous Carcinoma of the Larynx / Stage IV Verrucous Carcinoma of the Oral Cavity / Unspecified Adult Solid Tumor, Protocol Specific / Untreated Metastatic Squamous Neck Cancer With Occult Primary1
1CompletedTreatmentMalignant Lymphomas / Small Intestine Cancer / Unspecified Adult Solid Tumor, Protocol Specific1
1TerminatedTreatmentB-Cell Chronic Lymphocytic Leukemia / Leukemia, Prolymphocytic / Recurrent Small Lymphocytic Lymphoma / Refractory Chronic Lymphocytic Leukemia1
1Unknown StatusTreatmentUnspecified Adult Solid Tumor, Protocol Specific1
2TerminatedTreatmentCancer, Breast1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySolubleA19243
Predicted Properties
PropertyValueSource
Water Solubility0.0124 mg/mLALOGPS
logP2.08ALOGPS
logP2.78ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)7.55ChemAxon
pKa (Strongest Basic)7ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area174 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity184.11 m3·mol-1ChemAxon
Polarizability65.38 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Macrolactam / Vinylogous amide / Carbamic acid ester / Amino acid or derivatives / Carboxamide group / Ketone / Lactam / Carbonic acid derivative / Secondary alcohol / Cyclic ketone
show 22 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
tertiary amino compound, secondary amino compound, lactam, macrocycle, benzoquinones (CHEBI:65324)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Tpr domain binding
Specific 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. Under...
Gene Name
HSP90AA1
Uniprot ID
P07900
Uniprot Name
Heat shock protein HSP 90-alpha
Molecular Weight
84659.015 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. 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. [PubMed:17016423]
  3. 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. [PubMed:10592235]

Drug created on October 20, 2016 16:24 / Updated on December 01, 2017 17:35