17-DMAG
17-DMAG Uses, Dosage, Side Effects, Food Interaction and all others data.
17-DMAG 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 .
17-DMAG 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) . 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 .
| Trade Name | 17-DMAG |
| Generic | Alvespimycin |
| Alvespimycin Other Names | 17-DMAG, Alvespimycin, DMAG |
| Type | |
| Formula | C32H48N4O8 |
| Weight | Average: 616.7455 Monoisotopic: 616.347214532 |
| Protein binding | Reported to be minimal. |
| Groups | Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Investigated for use as an antineoplastic agent for solid tumors, advanced solid tumours or acute myeloid leukaemia.
How 17-DMAG works
17-DMAG 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 . 17-DMAG 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 .
Toxicity
17-DMAG 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
Volume of Distribution
At the maximum tolerated dose of 80mg/m^2, the mean Vd value is 385 L.
Elimination Route
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.
Half Life
The half-life across all dose levels ranged from 9.9 to 54.1 h (median, 18.2 h) .
Clearance
The mean clearance is 18.9 L/hr at the dose of 80mg/m^2.
Elimination Route
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 .
Innovators Monograph
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