1. Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy
- Author
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Jeffrey J. Jackson, Grant M. Shibuya, Buvana Ravishankar, Lavanya Adusumilli, Delia Bradford, Dirk G. Brockstedt, Cyril Bucher, Minna Bui, Cynthia Cho, Christoph Colas, Gene Cutler, Adrian Dukes, Xinping Han, Dennis X. Hu, Scott Jacobson, Paul D. Kassner, George E. Katibah, Michelle Yoo Min Ko, Urvi Kolhatkar, Paul R. Leger, Anqi Ma, Lisa Marshall, Jack Maung, Andrew A. Ng, Akinori Okano, Deepa Pookot, Daniel Poon, Chandru Ramana, Maureen K. Reilly, Omar Robles, Jacob B. Schwarz, Anton A. Shakhmin, Hunter P. Shunatona, Raashi Sreenivasan, Parcharee Tivitmahaisoon, Mengshu Xu, Thant Zaw, David J. Wustrow, and Mikhail Zibinsky
- Subjects
Mice, Knockout ,Mice ,eIF-2 Kinase ,Myeloid-Derived Suppressor Cells ,T-Lymphocytes ,Drug Discovery ,Animals ,Molecular Medicine ,Heme ,Protein Serine-Threonine Kinases - Abstract
General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK. In mice, compound
- Published
- 2022
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