Alvespimycin API Manufacturers

General Description:

Alvespimycin, identified by CAS number 467214-20-6, is a notable compound with significant therapeutic applications. 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 .

Indications:

This drug is primarily indicated for: Investigated for use as an antineoplastic agent for solid tumors, advanced solid tumours or acute myeloid leukaemia. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Alvespimycin undergoes metabolic processing primarily in: 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 . However in vivo and in vitro studies suggest that weak metabolism of alvespimysin occurs in humans. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Alvespimycin are crucial for its therapeutic efficacy: 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. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Alvespimycin is an important consideration for its dosing schedule: The half-life across all dose levels ranged from 9.9 to 54.1 h (median, 18.2 h) . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Alvespimycin exhibits a strong affinity for binding with plasma proteins: Reported to be minimal. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Alvespimycin from the body primarily occurs through: 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 . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Alvespimycin is distributed throughout the body with a volume of distribution of: At the maximum tolerated dose of 80mg/m^2, the mean Vd value is 385 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Alvespimycin is a critical factor in determining its safe and effective dosage: The mean clearance is 18.9 L/hr at the dose of 80mg/m^2. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Alvespimycin exerts its therapeutic effects through: 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) . 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 . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Alvespimycin functions by: 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 . 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 . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Alvespimycin 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, classified under the direct parent group Macrolactams. This compound is a part of the Organic compounds, falling under the Phenylpropanoids and polyketides superclass, and categorized within the Macrolactams class, specifically within the None subclass.

Categories:

Alvespimycin is categorized under the following therapeutic classes: Amides, HSP90 Heat-Shock Proteins, Lactams, Quinones. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Alvespimycin include:

• Water Solubility: Soluble