Inhibitor of Mastermind Recruitment-1 (IMR-1, 310456-65-6) disrupts the recruitment of Mastermind-like 1 to the Notch transcriptional activation complex (NTC) on chromatin, which attenuates Notch target gene transcription.1?IC50=26 μM (in vitro assay). IMR-1 inhibits the growth of Notch-dependent cell lines and attenuates the growth of patient-derived tumor xenografts. The ethyl ester is hydrolyzed by intracellular esterases which produces the free acid compound (IMR-1A), IC50=0.5 μM (in vitro?assay). Binding of IMR-1 to NTC is non-covalent and reversible.1
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].
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].
1) Austudilo?et al.?(2016),?The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis; Cancer Res.,?76?3593
