Waller Daniel D, Jansen Gregor, Golizeh Makan, Martel-Lorion Chloe, Dejgaard Kurt, Shiao Tze Chieh, Mancuso John, Tsantrizos Youla S, Roy René, Sebag Michael, Sleno Lekha, Thomas David Y
Department of Medicine, McGill University, 1001 Boulevard Décarie, Montréal, QC, H4A 3J1, Canada.
Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montréal, QC, H3G 1Y6, Canada.
Chembiochem. 2016 May 3;17(9):843-51. doi: 10.1002/cbic.201500485. Epub 2016 Mar 7.
The unfolded protein response (UPR) initiated by the transmembrane kinase/ribonuclease Ire1 has been implicated in a variety of diseases. Ire1, with its unique position in the UPR, is an ideal target for the development of therapies; however, the identification of specific kinase inhibitors is challenging. Recently, the development of covalent inhibitors has gained great momentum because of the irreversible deactivation of the target. We identified and determined the mechanism of action of the Ire1-inhibitory compound UPRM8. MS analysis revealed that UPRM8 inhibition occurs by covalent adduct formation at a conserved cysteine at the regulatory DFG+2 position in the Ire1 kinase activation loop. Mutational analysis of the target cysteine residue identified both UPRM8-resistant and catalytically inactive Ire1 mutants. We describe a novel covalent inhibition mechanism of UPRM8, which can serve as a lead for the rational design and optimization of inhibitors of human Ire1.
