Background and overview[1]
In many cancers, aberrant Notch activity has been shown to play a role in the initiation and maintenance of tumor phenotypes and cancer stem cells, which may implicate its additional involvement in metastasis and resistance to therapy. Therefore, Notch is an attractive target for cancer therapy, but various potential targets in this pathway have not been fully studied. To date, no small molecule inhibitors directly target the intracellular Notch pathway or the assembly of transcriptional activation complexes. Some studies have used computer-aided design of a small molecule inhibitor called Mastermind Recruitment-1 inhibitor (IMR-1, that is, [2-methoxy-4-[(4-oxo-2-thio-5 -thiazolidin subunit)methyl]phenoxy]ethyl acetate), which disrupts the recruitment of Mastermind-like 1 to the Notch transcriptional activation complex on chromatin, thereby attenuating the transcription of Notch target genes. Furthermore, [2-methoxy-4-[(4-oxo-2-thio-5-thiazolidinylidene)methyl]phenoxy]ethyl acetate inhibited the growth of Notch-dependent cell lines and significantly Eliminate the growth of patient-derived tumor xenografts. Taken together, the findings suggest that a novel class of Notch inhibitors targeting the transcriptional activation complex may represent a new paradigm for Notch-based anticancer therapies.
Apply[1]
The core molecular scaffold of [2-methoxy-4-[(4-oxo-2-thio-5-thiazolidinylidene)methyl]phenoxy]ethyl acetate is a thiazolidinone. Thiazolidinones are heterocyclic compounds containing a rhodanine moiety, and many thiazolidinones have been clinically successful. However rhodanine may cause non-specific interactions due to its potential reactivity and therefore rhodanine is known as a PAIN (pan-assay interference) molecule. [2-Methoxy-4-[(4-oxo-2-thio-5-thiazolidinylidene)methyl]phenoxy]ethyl acetate shows specificity for Notch target genes and in-use IMR -1 No general toxicity was observed during in vivo treatment. In conclusion, [2-methoxy-4-[(4-oxo-2-thio-5-thiazolidinylidene)methyl]phenoxy]ethyl acetate is a new class of Notch inhibitors with potential. This class of inhibitors may fill an unmet need for therapeutics targeting the Notch signaling pathway, providing specific inhibition of the Notch transcriptional activation complex, which may complement and/or provide an alternative to current therapeutic approaches.
Main reference materials
[1] The small molecule IMR-1 inhibits the notch transcriptional activation complex to suppress tumorigenesis
