6XDD

Crystal structure of IRE1 in complex with G-3053

Summary for 6XDD

• Entry DOI: 10.2210/pdb6xdd/pdb
• Descriptor: Serine/threonine-protein kinase/endoribonuclease IRE1, 4-[(trans-4-aminocyclohexyl)amino]-N-(6-chloro-3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)thieno[3,2-d]pyrimidine-7-carboxamide (3 entities in total)
• Functional Keywords: kinase, rnase, inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 100824.98

Authors

Ackerly-Wallweber, H.,Wang, W. (deposition date: 2020-06-10, release date: 2021-04-21, Last modification date: 2024-11-20)

Primary citation

Beveridge, R.E.,Wallweber, H.A.,Ashkenazi, A.,Beresini, M.,Clark, K.R.,Gibbons, P.,Ghiro, E.,Kaufman, S.,Larivee, A.,Leblanc, M.,Leclerc, J.P.,Lemire, A.,Ly, C.,Rudolph, J.,Schwarz, J.B.,Srivastava, S.,Wang, W.,Zhao, L.,Braun, M.G.
Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1 alpha Inhibitory Activity.
Acs Med.Chem.Lett., 11:2389-2396, 2020

PubMed Abstract: Amino-quinazoline BRaf kinase inhibitor was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1α 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 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.

PubMed: 33335661
DOI: 10.1021/acsmedchemlett.0c00344

Experimental method

X-RAY DIFFRACTION (2.4 Å)