Proteasome inhibitors/2. generation

Current situation
The following substances are currently in clinical trials : MLN9708 (Millenimu Pharmaceuticals), CEP-18770 (Cephalon & Cell Therapeutics Europe), Carfilzomib (Proteolix) and  NPI-0052 (Nereus Pharmaceuticals).

MLN9708
It is chemically similar to bortezomib and, like bortezomib, inhibits the 20S proteasome reversibly (after some time it is released from its binding site on the 20S proteasome). Compared to bortezomib, it is also effective when administered orally. Four ongoing clinical trials (phase 1-2) of this agent (multiple myeloma, solid tumors, lymphoma) can be found at NCI.

CEP-18770
Also a reversible 20S proteasome inhibitor (again chemically similar to bortezomib), but given intravenously. Currently, there is only one clinical trial of this substance (phase 2, multiple myeloma).

Both other agents are irreversible 20S proteasome inhibitors and belong to completely different chemical classes: unlike bortezomib, which is derived from a combination of monoalkylboronic acid and a dipeptide, carfilzomib is a combination of an epoxy ketone and a tetrapeptide, and NPI-0052 is a bicyclic γ-lactam-β-lactone.

NPI-0052
It is also known as salinosporamide A and was originally isolated from a single marine bacterium. Four ongoing clinical trials (intravenous, phase 1, multiple myeloma, solid tumors, lymphomas) can be found on the NCI website for this substance.

Carfilzomib
It is being tested in eight clinical trials (intravenous, phase 1-2, lymphomas, leukemia, solid tumors), in combination with other drugs even in phase 3 in patients with multiple myeloma. However, VELCADE (bortezomib) still remains the only clinically used proteasome inhibitor.

Future
However, Hershk's original idea in his conversation with Adams was not to stop protein degradation per se. 20S Proteasome Inhibitors interfere with too many cellular processes at once. Rather, Hershko was thinking about how to influence the degradation of specific selected proteins known to play a significant role in the development and progression of cancer. For such an approach, it is necessary to inhibit specific E3 ligases that decide on ubiquitination and degradation of these proteins.

MLN4924
It is the first such inhibitor, entered clinical trials very recently and comes from Millenium Pharmaceuticals. In fact, it is not an inhibitor of an E3 ligase directly, but rather a NAE enzyme inhibitor (NEDD8-activating enzyme), which regulates one group of E3 ligases. In this sense, MLN4924 represents a completely unique approach to the treatment of cancer that has not been tried before. Four clinical trials of this substance can be found on the NCI website (intravenous, phase 1, melanoma, leukemia, lymphomas, multiple myeloma, and also solid tumors).

Related Articles

 * Degradative system of the cell
 * Ubiquitination
 * Deubiquitination
 * Proteasome and its inhibitors
 * Studies on Proteasome Inhibitors
 * History of Proteasome Inhibitors
 * Antabuse

Source

 * ws:Inhibitory proteazomu/2. generace