Aberrant activation of the Notch pathway plays a key role in initiation, development, and metastasis of cancers. The inhibitor of mastermind recruitment-1 (IMR-1) is a small-molecule inhibitor of the Notch transcriptional activation complex with an IC50 value of 26μM. IMR-1A is the acid metabolite of IMR-1, exhibiting 50-fold higher potency for Notch than IMR-1, with an IC50 value of 0.5μM. IMR-1A also showed significantly higher affinity to the intracellular domain of Notch (NICD) than IMR-1 (KD: 2.9±0.6μM vs. 11±3μM). Treatment of Notch-dependent cell lines OE33 and 786-0 with IMR-1 (25μM) inhibited Notch-directed transcriptional activation via blocking the occupancy of Maml1 to the Notch transcriptional activation complex, without changing the level of NICD in cells. IMR-1 at a dosage of 15mg/kg blocked tumor establishment in nude mice inoculated with OE19 human esophageal adenocarcinoma cells. In patient-derived esophageal adenocarcinoma xenograft (PDX) models, IMR-1 treatment at 15mg/kg significantly abrogated tumor growth and reduced the expression of Notch target genes compared with DMSO-treated controls[3].
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