6xdb | pdb_00006xdb
Crystal structure of IRE1a in complex with G-6904
Structural highlights
FunctionERN1_HUMAN Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto-activation. The active endoribonuclease domain splices XBP1 mRNA to generate a new C-terminus, converting it into a potent unfolded-protein response transcriptional activator and triggering growth arrest and apoptosis.[1] [2] [3] [UniProtKB:Q9EQY0] Publication Abstract from PubMedAmino-quinazoline BRaf kinase inhibitor 2 was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1alpha. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1alpha potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1alpha cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1alpha was then targeted to build in selectivity over BRaf which instead possesses a histidine in this position (His539). Torsional angle analysis revealed that the quinazoline hinge binder core was ill-suited to accommodate the required conformation to effectively reach Glu651, prompting a change to the thienopyrimidine hinge binder. Resulting analogues such as 25 demonstrated good IRE1alpha cellular potency and imparted more than 1000-fold decrease in BRaf activity. Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1alpha Inhibitory Activity.,Beveridge RE, Wallweber HA, Ashkenazi A, Beresini M, Clark KR, Gibbons P, Ghiro E, Kaufman S, Larivee A, Leblanc M, Leclerc JP, Lemire A, Ly C, Rudolph J, Schwarz JB, Srivastava S, Wang W, Zhao L, Braun MG ACS Med Chem Lett. 2020 Oct 16;11(12):2389-2396. doi:, 10.1021/acsmedchemlett.0c00344. eCollection 2020 Dec 10. PMID:33335661[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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