2. Academic Validation
  3. Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity

Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity

  • ACS Med Chem Lett. 2020 Oct 16;11(12):2389-2396. doi: 10.1021/acsmedchemlett.0c00344.
Ramsay E Beveridge 1,  Heidi Ackerly Wallweber 2,  Avi Ashkenazi 2,  Maureen Beresini 2,  Kevin R Clark 2,  Paul Gibbons 2,  Elise Ghiro 1,  Susan Kaufman 2,  Alexandre Larivée 1,  Melissa Leblanc 1,  Jean-Philippe Leclerc 1,  Alexandre Lemire 1,  Cuong Ly 2,  Joachim Rudolph 2,  Jacob B Schwarz 2,  Sanjay Srivastava 1,  Weiru Wang 2,  Liang Zhao 1,  Marie-Gabrielle Braun 2
Affiliations

Affiliations

  • 1 Paraza Pharma Inc., 2525 Ave. Marie-Curie, Montreal, QC, Canada H4S 2E1.
  • 2 Genentech Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
PMID: 33335661 DOI: 10.1021/acsmedchemlett.0c00344
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.

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