KIRA6 | IRE1α inhibitor

KIRA6 (1589527-65-0) is an allosteric inhibitor of the endoplasmic reticulum protein IRE1α.¹ It inhibits IRE1α kinase activity (IC₅₀ = 0.60 µM), XBP1 RNA cleavage, Ins2 RNA cleavage, and oligomerization. KIRA6 prevented cell death during ER stress/UPR in vivo. It reduced stress-induced inflammation caused by immunogenic cell death via targeting of HSP60.² KIRA6 abolished neuroinflammation and neuronal cell death caused by PAD4 overexpression in traumatic brain injury.³ It also was shown to block leukotriene biosynthesis in human phagocytes⁴ and inhibit mast cells⁵. KIRA6 blocked the induction of myeloid-derived suppressor cells and overcame resistance to anti-PD-1 therapy in 4T1 tumor cells.⁶

References/Citations:

1. Ghosh et al. (2014), Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress; Cell, 158 534
2. Rufo et al. (2022), Stress-induced inflammation evoked by immunogenic cell death is blunted by the IRE1alpha kinase inhibitor through HSP60 targeting; Cell Death Differ. , 29 230
3. Shi et al. (2023), Inhibition of neutrophil extracellular trap formation ameliorates neuroinflammation and neuronal apoptosis via STING-dependent IRE1α/ASK1/JNK signaling pathway in mice with traumatic brain injury; J. Neuroinflammation, 20 222
4. Tang et al. (2022), The IRE1alpha Inhibitor KIRA6 Blocks Leukotriene Biosynthesis if Human Phagocytes; Front. Pharmacol. , 13 806240
5. Wunderle et al. (2025), KIRA6 is an Effective and Versatile Mast Cell Inhibitor of IgE-mediated Activation; Eur. J. Immunol., 55 e202451348
6. Chen et al. (2025), KIRA6 restrains the generation of myeloid-derived suppressor cells and overcomes resistance to anti-PD-1 therapy; Cell Death Dis. , online ahead of print