Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch

Abstract

The membrane-bound transcription factor ATF6α plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6α promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6α signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6α signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6β or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6α and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination.DOI: http://dx.doi.org/10.7554/eLife.11878.001

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

“…Additionally, FLI-06 hindered DHC-induced ATF6 from appearing in the nucleus, just as it had for Tg-induced ATF6 (Figure 4F). In a further similarity, treatment of cells with Ceapin A7, an inhibitor of Tg activation of ATF6 (Gallagher et al, 2016; Gallagher and Walter, 2016), also blocked DHC activation of ATF6 (figure 4C–4E, S4B, and S4C). Lastly, we asked whether DHC activation must induce cleavage of the transmembrane domain of ATF6 for effective activation (freeing of the N-terminal transcription factor domain).…”

The unfolded protein response regulator ATF6 promotes mesodermal differentiation

“…To determine whether the effects of AA147 on hESC differentiation required ATF6 activation, we treated hESCs with the small-molecule ATF6 inhibitor, Ceapin-A7 (38). Ceapin-A7 inhibits ATF6 signaling by trapping the full-length ATF6 molecule in the ER, thereby preventing the generation of ATF6(N) transcriptional activator (39).…”

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

“…The current therapeutic and pharmacological strategies that target ER proteostasis in cancer focus either on exacerbating ER stress to a level with which tumor cells cannot cope and therefore die or on decreasing the adaptive capacity of the tumor cells, leading to loss of selective advantage and tumor death. Over the past 5 years, several inhibitors of the three UPR sensors have been developed (Table 1) (44,58,(126)(127)(128)(129)(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140). Some new drugs are now tested to specifically target particular UPR sensors to kill cancer cells or sensitize them to commonly used treatments.…”

“…The protein disulfide isomerase PDIA5 is critical for ATF6 activation, enabling its export from ER under stress conditions; genetic or pharmacological inhibition of the PDIA5/ATF6 axis (using the PDI inhibitor 16F16) sensitizes leukemia cells to imatinib treatment (58). Similarly, in a more recent work, it was demonstrated that ceapins, a class of pyrazole amides, blocked ATF6 signaling in response to ER stress by trapping it in the ER (126,127). On the other hand, Plate et al identified two nontoxic small molecules, compounds 147 and 263, which selectively activated the ATF6 branch of the UPR (128).…”