Identifying new mechanisms of action is vital for pre-clinical and clinical trials.
- Trabectedin and lurbinectedin
Trabectedin and Lurbinectedin are two selective inhibitors of trans-activated RNA polymerase II transcription. They selectively block the elongation phase of messenger RNA synthesis performed by RNA polymerase II. They do not inhibit RNA polymerase I or mitochondrial RNA polymerase, nor do they affect basal transcription: their action mechanism very selectively inhibits RNA polymerase II transcription. This is reflected in clinical results, since some tumors present transcriptional addiction (e.g. translocation-related sarcomas, small cell lung cancer, and triple negative breast cancer). These are clear examples of tumors that are sensitive to lurbinectidin.
The target of plitidepsin is the eEF1A2 protein. The bonding of plitidepsin to this protein blocks its pro-oncogenic property and impedes the transportation of the misfolded proteins, which are toxic to the tumor, to the proteasome for their destruction. It also inhibits the activation of the aggresome by eEF1A2 and the destruction of the aggresome in the lysosome. This provokes an excess of misfolded proteins, this causing cell death through apoptosis. Other treatments are complementary to plitidepsin and they are going to block the proteasome or the cereblon that identifies the misfolded proteins.
This compound inhibits tubulin polymerization. These proteins form part of the cell’s skeleton (the cytoskeleton). As a result, the cytoskeleton becomes degraded and the tumor cells lose the capacity to mobilize and divide.