An inhibitor of Maml1 recruitment to chromatin
IC50: 26 μmol/L
IMR-1 is a inhibitor of Notch pathway.
Aberrant Notch activity has been reported to play a important role in the initiation and maintenance of the neoplastic phenotype and in various cancer stem cells, which alludes to its additional involvement in metastasis and resistance.
In vitro: In order to determine the effect of IMR-1 on the assembly of the Notch ternary complex (NTC) in cells, Notch-dependent cell lines OE33 and 786-0 were treated with IMR-1 or DAPT. Results showed that treatment of OE33 and 786-0 with IMR-1 could decrease the occupancy of Maml1 on the HES1 promoter but, in contrast to DAPT, IMR-1 treatment could not affect the occupancy of Notch1 on the HES1 promoter. In addition, western blot analyses indicated that IMR-1 treatment did not change the cellular levels of NICD [1].
In vivo: Animal study showed that treatment of mice with 15 mg/kg IMR-1 could readily block tumor establishment. Moreover, IMR-1 treatment at 15 mg/kg caused no observable adverse effects on the animal. In two independent PDX models, IMR-1 could significantly abrogate the tumor growth to a similar level achieved with DAPT treatment, without any significant weight loss or other visible signs of adverse effects in the treated mice [1].
Clinical trial: Up to now, IMR-1 is still in the preclinical development stage.
Reference:
[1] Astudillo L,Da Silva TG,Wang Z,et al.? The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis. Cancer Res.2016 Jun 15;76(12):3593-603.
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