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Carfilzomib- History, Structure and Mechanism of Action

Carfilzomib is a medication that aims to cure bone marrow cancer. It is a tetrapeptide epoxyketone and an epoxomicin analogue developed by Onyx Pharmaceuticals.

The common abbreviation for Carfilzomib is CFZ and it is sold under the brand name Kyprolis. The route of administration for Carfilzomib is intravenous.

History of Carfilzomib

Carfilzomib is derived from a natural substance called epoxomicin that inhibits proteasome. A laboratory invented a more specific derivative of epoxomicin that was named YU101 and was further developed to invent a new compound that could have potential uses as a drug for humans known as Carfilzomib.

After multiple clinical trials, it was approved to be used as a drug to treat patients with relapsed and refractory multiple myeloma who had received previous therapy including bortezomib and lenalidomide. Carfilzomib was approved by FDA as an injectable antineoplastic agent on July 20, 2012.  The approximate cost of the drug is $10,000 for a 28-day cycle.

Structure of Carfilzomib

Carfilzomib is a crystalline substance that is insoluble in water and slightly soluble in acidic conditions.

The molecular formula of Carfilzomib is C40H57N5O7. It has a molecular weight of 719.909 and a Monoisotopic weight of 719.425.

Carfilzomib structure inhibits and binds to the chymotrypsin-like activity of the proteasome core subunit. The responsibility of degrading a large variety of cellular proteins is carried out by a protease complex.

An accumulation of polyubiquitinated proteins is the result of the inhibition of proteasome-mediated proteolysis, which could lead to induction of apoptosis, cell cycle arrest, and inhibition of tumour growth.

 

Mechanism of Action of Carfilzomib

Carfilzomib being a tetrapeptide epoxyketone proteasome inhibitor, irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib was seen to possess proapoptotic and antiproliferative activities in hematologic tumour cells.

The proteasome is a therapeutic target in multiple myeloma. Even when the clonal heterogeneity evolution changes following exposure to therapies, the proteasomes still exist within the myeloma cells. Carfilzomib inhibits proteasomal activity, preventing them from recycling excess proteins. This leads to a build of protein levels inside the cell which results in myeloma cell apoptosis.

Intravenous Carfilzomib administration gave results like suppression of proteasome chymotrypsin activities after the first dose of cycle 1. Based on the Carfilzomib mechanism of action, the usage of Kyprolis during pregnancy can harm the fetus as also found in animals.

Research suggests that Carfilzomib in fact has more potency than Bortezomib- a drug that was earlier approved for multiple myeloma treatment.

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