Beveridge, Ramsay E.; Wallweber, Heidi Ackerly; Ashkenazi, Avi; Beresini, Maureen; Clark, Kevin R.; Gibbons, Paul; Ghiro, Elise; Kaufman, Susan; Larivee, Alexandre; Leblanc, Melissa; Leclerc, Jean-Philippe; Lemire, Alexandre; Ly, Cuong; Rudolph, Joachim; Schwarz, Jacob B.; Srivastava, Sanjay; Wang, Weiru; Zhao, Liang; Braun, Marie-Gabrielle published the artcile< Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity>, Application In Synthesis of 1046832-21-6, the main research area is preparation BRaf amino thieno pyrimidine derivative IRE1 inhibitor cancer.
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 crystallog. 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 anal. 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 analogs such as 25 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.
ACS Medicinal Chemistry Letters published new progress about Antitumor agents. 1046832-21-6 belongs to class pyrazoles-derivatives, and the molecular formula is C11H19BN2O2, Application In Synthesis of 1046832-21-6.
Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics