Carfilzomib Proteasome Inhibitors for Treatment of Multiple Myeloma Patients .pdf
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Carfilzomib: Proteasome Inhibitors for Treatment of
Multiple Myeloma Patients
There were 138,509 new multiple myeloma (MM) cases worldwide in 2016; in the
United States, 30,770 projected cases occurred in 2018. The global incidence has
increased sharply in recent decades, in part due to aging populations.
For newly diagnosed MM (NDMM) patients, the introduction of proteasome
inhibitors (PIs) and immunomodulatory drugs (IMiDs) has improved treatment
responses versus older therapies. Carfilzomib is a novel, highly selective tetrapeptide
epoxyketone proteasome inhibitor for use in patients with multiple myeloma who
have received at least two prior therapies and have demonstrated disease
progression on or within 60 days of completion of the last therapy.
It was developed by Onyx and was approved by the US Food and Drug
Administration (FDA) for marketing on July 20, 2012. Later it was approved by the
European Medicines Agency (EMA) on November 19, 2015, and approved by the
Japan Pharmaceuticals and Medical Device Comprehensive Agency (PMDA) on July 4,
2016. In August 2013, Amgen acquired Onyx Pharmaceuticals and has since sold the
drug under the trade name Kyprolis®.
Carfilzomib is a synthetic tetrapeptide consisting of morpholin-4-acetyl, L-2-amino-4phenylbutanoyl, L-leucyl and L-phenylalanyl residues joined in sequence with the Cterminus connected to the amino group of (2S)-2-amino-4-methyl-1-[(2R)-2methyloxiran-2-yl]-1-oxopentan-1-one via an amide linkage.
Mechanism of Action: How Does Carfilzomib Work?
Carfilzomib irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S
catalytic core subunit of the proteasome. Proteasome is part of the cellular
machinery and has many functions within the cell, such as it helps to control the
level of many of the proteins that help to regulate cell division and cell survival. By
interfering with its function this can lead to apoptosis (cell suicide). In the laboratory,
it has been shown that cancer cells are more susceptible to the effects of
proteasome inhibitors than normal cells are.
Carfilzomib exerts its anti-myeloma activity through a variety of actions, including
induction of unfolded protein stress response, down-regulation of NF-κB prosurvival
activity, modification of bone turnover and the bone marrow microenvironment,
leading to increased bone strength compromised microenvironmental support for
myeloma cells, and induction of immunogenic myeloma cell death through increased
natural kill cell-mediated MM-cell lysis and enhanced antigen presentation.
Carfilzomib has a different structure (tetrapeptide epoxyketone) from the first
generation PI bortezomib (dipeptide boronate). Preclinical studies have shown that
carfilzomib can overcome the resistance of bortezomib without reducing neurite
length or inhibiting non-proteasomal targets such as HtrA2 / Omi, which was
observed in bortezomib. Compared to bortezomib, carfilzomib causes deeper,
longer-lasting proteasome inhibition.
Carfilzomib Mechanism of Action, Image Resource: pharmacodia.com
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