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Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity
Authors:Ramsay E. Beveridge,Heidi Ackerly Wallweber,Avi Ashkenazi,Maureen Beresini,Kevin R. Clark,Paul Gibbons,Elise Ghiro,Susan Kaufman,Alexandre Larivé  e,Melissa Leblanc,Jean-Philippe Leclerc,Alexandre Lemire,Cuong Ly,Joachim Rudolph,Jacob B. Schwarz,Sanjay Srivastava,Weiru Wang,Liang Zhao,Marie-Gabrielle Braun
Affiliation:Paraza Pharma Inc., 2525 Ave. Marie-Curie, Montreal, QC, Canada, H4S 2E1;Genentech Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States
Abstract:Amino-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 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 25 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.
Keywords:IRE1α  , BRaf, kinase, unfolded protein response
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