Proteasome inhibitors
Proteasome inhibitors are small-molecule drugs designed to target the proteasome, a crucial protein complex that degrades unwanted or damaged proteins within cells. This process, facilitated by ubiquitination, is essential for maintaining cellular balance and promoting healthy cell function. By interfering with the proteasome's ability to perform its role, these inhibitors can induce death in rapidly dividing cancer cells, making them particularly relevant in cancer therapies. Notable examples include bortezomib, the first proteasome inhibitor approved by the FDA for cancer treatment, which is administered through intravenous injection. Additional proteasome inhibitors such as carfilzomib and the oral option ixazomib have also been developed for conditions like multiple myeloma. While generally well tolerated, proteasome inhibitors can have side effects, including weakness, gastrointestinal issues, and peripheral neuropathy. Ongoing research explores other compounds with proteasome inhibitory activity, though not all are currently used for cancer treatment. This class of drugs represents a significant advancement in targeted cancer therapies, particularly for hematological malignancies.
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Proteasome inhibitors
ATC CODE: 101XX
DEFINITION: Proteasome inhibitors are small-molecule drugs that target the proteasome, a large protein complex responsible for degrading unwanted proteins in the cell. Certain proteins are marked for proteasomal degradation by ubiquitination, which adds multiple ubiquitin molecules to the protein. Ubiquitinated proteins are recognized by the proteasome, allowing for the degradation of specifically targeted proteins. Cells rely on the proteasome to maintain a proper balance of particular proteins and remove damaged protein. Because the proteasome is essential for many cellular processes, including cell division and survival, it is an attractive target for actively growing cancer cells.
Cancers treated: Multiple myeloma, mantle cell lymphoma, lung cancer
Subclasses of this group: Synthetic inhibitors, natural inhibitors
Delivery routes: Intravenous (IV) injection
How these drugs work: Proteasome inhibitors are targeted therapies specific to the proteasome protein complex. These agents bind to the proteasome, impairing its ability to degrade proteins in the cell. Because degradation of excess and damaged proteins is necessary for normal cellular processes such as cell proliferation, these inhibitors can induce death in actively dividing malignant cells.
The first proteasome inhibitor to be approved by the US Food and Drug Administration (FDA) to treat patients with cancer was bortezomib (Velcade). Bortezomib is administered by IV injection at a recommended dosage of twice-weekly for two weeks, followed by a rest period. Several cycles of this therapy may be given. In 2012, carfilzomib (Kyprolis) was approved for use in patients with multiple myeloma that has not responded to other treatments. Carfilzomib is also administered intravenously, twice-weekly for three weeks followed by twelve days of rest. In 2015, the FDA approved ixazomib, the first oral proteasome inhibitor, which is also used by multiple myeloma patients looking for a second line of treatment.
Other compounds have been discovered to have proteasome inhibitory activity, but these agents are not currently indicated for cancer treatment. Ritonavir is an antiretroviral drug used in human immunodeficiency virus (HIV) therapy. Preclinical studies have shown that ritonavir may be active against brain tumor cells. Lactacystin is a natural proteasome inhibitor primarily used in laboratory settings. Clinical trials of these two drugs remain underway.
Side effects: Bortezomib, the first proteasome inhibitor to be approved as an antineoplastic agent, is generally safe and well tolerated. The predominant side effects noted with bortezomib therapy are weakness, diarrhea and constipation, nausea and vomiting, and peripheral neuropathy, or a tingling in the hands and feet. Additionally, myelosuppression, such as thrombocytopenia and neutropenia, has been noted. Carfilzomib has similar side effects; heart failure and renal failure have also been observed in rare cases.
Bibliography
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Yong, Kwee, et al. "The Start of a New Wave: Developments in Proteasome Inhibition in Multiple Myeloma." European Journal of Haematology, vol. 101, no. 2, 2018, pp. 220-236, doi.org/10.1111/ejh.13071. Accessed 30 June 2024.