BI 5700, a Selective Chemical Inhibitor of I B Kinase 2, Specifically Suppresses Epithelial-Mesenchymal Transition and Metastasis in Mouse Models of Tumor Progression

Abstract

Increasing evidence suggests that processes termed epithelial-mesenchymal transitions (EMTs) play a key role in therapeutic resistance, tumor recurrence, and metastatic progression. NF-κB signaling has been previously identified as an important pathway in the regulation of EMT in a mouse model of tumor progression. However, it remains unclear whether there is a broad requirement for this pathway to govern EMT and what the relative contribution of IKK family members acting as upstream NF-κB activators is toward promoting EMT and metastasis. To address this question, we have used a novel, small-molecule inhibitor of IκB kinase 2 (IKK2/IKKβ), termed BI 5700. We investigated the role of IKK2 in a number of mouse models of EMT, including TGFβ-induced EMT in the mammary epithelial cell line EpRas, CT26 colon carcinoma cells, and 4T1 mammary carcinoma cells. The latter model was also used to evaluate in vivo activities of BI 5700.We found that BI 5700 inhibits IKK2 with an IC(50) of 9 nM and was highly selective as compared to other IKK family members (IKK1, IKKε, and TBK1) and other kinases. BI 5700 effectively blocks NF-κB activity in EpRas cells and prevents TGFβ-induced EMT. In addition, BI 5700 reverts EMT in mesenchymal CT26 cells and prevents EMT in the 4T1 model. Oral application of BI 5700 significantly interferes with metastasis after mammary fat-pad injection of 4T1 cells, yielding fewer, smaller, and more differentiated metastases as compared to vehicle-treated control animals. We conclude that IKK2 is a key regulator of both the induction and maintenance of EMT in a panel of mouse tumor progression models and that the IKK2 inhibitor BI 5700 constitutes a promising candidate for the treatment of metastatic cancers.

IKKα controls canonical TGFβ–SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in Panc1 cells

“…Furthermore, excellent work using a combined in vitro/in vivo EMT model of mammary carcinogenesis (the TGF-dependent EpH4/EpRas model) revealed the essential contribution of NFB to the induction of EMT, maintenance of the mesenchymal phenotype, and metastasis in vivo (Huber et al, 2004a;Huber et al, 2004b). Consistently, the small-molecule IKK inhibitor BI 5700 interfered with NFB-driven EMT and metastasis (Huber et al, 2010). To investigate the role of NFB in a well-established TGF-dependent EMT model of Panc1 cells (Ellenrieder et al, 2001), we used RNA interference (RNAi).…”

Development and characterization of a reliable mouse model of colorectal cancer metastasis to the liver

“…These findings are supported by the significantly higher abilities for invasion and migration of CT26-FL3 compared to CT26 cells, as measured by the matrigel-coated Boyden Chamber and wound healing assays. Although the CT26 and CT26-FL3 cells show constitutive expression of both epithelial and mesenchymal markers when grown in culture [41], tumors from CT26-FL3 expressed higher levels of markers associated with mesenchymal cells, further underscoring their enhance capabilities for migration and invasion.…”

A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets

“…Selectivity data for IMD1041, IMD0254 and BMS345541 are not available, unfortunately. A better characterized inhibitor is BI5700, a 9 nM IKBKB inhibitor that essentially only weakly hits off‐target IKK1 and FLT3 in a 59‐kinase profile, and has a cellular IC 50 of 290 nM for IκBα phosphorylation (Huber et al ., 2010). However, the best IKBKB inhibitor is MLN120B, which is related to PS1145 and was recently profiled (Davis et al ., 2011), revealing 50‐fold selectivity over IKK1 and a very low selectivity entropy of 0.7 (Table 3).…”