Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung

Abstract

Endoplasmic reticulum stress (ER stress) has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a disease of progressive fibrosis and respiratory failure. ER stress activates a signaling pathway called the unfolded protein response (UPR) that either restores homeostasis or promotes apoptosis. The bifunctional kinase/RNase IRE1α is a UPR sensor/effector that promotes apoptosis if ER stress remains high and irremediable (i.e., a “terminal” UPR). Using multiple small molecule inhibitors against IRE1α, we show that ER stress-induced apoptosis of murine alveolar epithelial cells can be mitigated in vitro. In vivo, we show that bleomycin exposure to murine lungs causes early ER stress to activate IRE1α and the terminal UPR prior to development of pulmonary fibrosis. Small-molecule IRE1α kinase-inhibiting RNase attenuators (KIRAs) that we developed were used to evaluate the contribution of IRE1α activation to bleomycin-induced pulmonary fibrosis. One such KIRA—KIRA7—provided systemically to mice at the time of bleomycin exposure decreases terminal UPR signaling and prevents lung fibrosis. Administration of KIRA7 14 days after bleomycin exposure even promoted the reversal of established fibrosis. Finally, we show that KIRA8, a nanomolar-potent, monoselective KIRA compound derived from a completely different scaffold than KIRA7, likewise promoted reversal of established fibrosis. These results demonstrate that IRE1α may be a promising target in pulmonary fibrosis and that kinase inhibitors of IRE1α may eventually be developed into efficacious anti-fibrotic drugs.

The role of the androgen receptor as a driver and mitigator of cellular stress

“…PERK inhibition (dark blue): GSK2656157 has been shown to decrease transmissible ER stress affecting metastasis, while ISRIB mediated PERK inhibition upregulates translation compounding anti-oncogenic misfolded protein mediated stress (Guthrie et al 2016, Rodvold et al 2017. IRE1 inhibition (Red): KIRAs have been shown to decrease fibrosis affecting motility (Thamsen et al 2019), sunitinib has been investigated in clinical trials as an anti-angiogen (https://clinicaltrials.gov/ct2/ show/NCT03025893; Jha et al 2011), while 4μ8C impacts autophagy by decreasing ERAD components (Erzurumlu & Ballar 2017). MKC8866 was shown to block c-Myc signalling (Sheng et al 2019) and toyocamycin lead to an upregulation of ROS formation impacting survival (Park et al 2017) in prostate cancer models.…”

Selective enhancement of cardiomyocyte efficiency results in a pernicious heart condition

“…It is also interesting to note the higher prevalence of cardiac fibrosis among endurance athletes where enhanced cardiac performance is required [38][39][40]. UPR activation in cardiac fibroblasts results in release of pro-inflammatory cytokines, increased deposition of collagen and other extracellular matrix proteins [41] and contributes to a process of phenotypic remodelling [17,42,43]. The increased mechanical load in Cardiac CRT+ hearts caused by the enhanced contractility of Cardiac CRT+ cardiomyocytes imposes mechanical stress on neighboring cardiac fibroblasts, and we demonstrated here experimentally that the mechanical stress experienced by cardiac fibroblasts simulated ex vivo by stretching of the cultured fibroblasts caused activation of IRE1α signaling associated with activation of cardiac fibrosis.…”

Control of Protein Homeostasis in the Early Secretory Pathway: Current Status and Challenges

“…For instance, kinase-inhibiting RNase attenuators (KIRAs) were developed to inhibit the IRE1 arm of the UPR. KIRA6 and KIRA8 were shown recently to inhibit IRE1a in vivo and promote cell survival during ER-stress conditions [123,124]. In addition, other compounds that target the IRE1 endoribonuclease domain, such as toyocamycin, STF-083010, 4µ8C, MKC-3946 and B-I09, are also highly used in different diseases models.…”