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
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 Ko, Urvi Kolhatkar, Paul R. Leger, Anqi Ma, Lisa A. Marshall, Jack Maung, Andrew A. Ng, Akinori Okano, Deepa Pookot, Daniel Poon, Chandru Ramana, Maureen K. Reilly, Omar Robles, Jacob B. Schwarz, Anton Shakhmin, Hunter P. Shunatona, Raashi Sreenivasan, Parcharee Tivitmahaisoon, Mengshu Xu, Thant Zaw, David J. Wustrow, Mikhail Zibinsky
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 39 engages GCN2 at levels ≥80% with an oral dose of 15 mg/kg BID. We also demonstrate the ability of compound 39 to alleviate MDSC-related T cell suppression and restore T cell proliferation, similar to the effect seen in MDSCs from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI) as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced by treatment with compound 39 demonstrating the complementarity of these two mechanisms.