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

Q1 · MEDICINE

Article

Author: Ng, Andrew A. ; Jackson, Jeffrey J. ; Zaw, Thant ; Jacobson, Scott ; Ravishankar, Buvana ; Bradford, Delia ; Adusumilli, Lavanya ; Ramana, Chandru ; Han, Xinping ; Poon, Daniel ; Colas, Christoph ; Robles, Omar ; Dukes, Adrian ; Zibinsky, Mikhail ; Hu, Dennis X. ; Bucher, Cyril ; Brockstedt, Dirk G. ; Shakhmin, Anton A. ; Bui, Minna ; Okano, Akinori ; Ma, Anqi ; Cutler, Gene ; Katibah, George E. ; Marshall, Lisa ; Ko, Michelle Yoo Min ; Schwarz, Jacob B. ; Reilly, Maureen K. ; Sreenivasan, Raashi ; Leger, Paul R. ; Kolhatkar, Urvi ; Kassner, Paul D. ; Cho, Cynthia ; Tivitmahaisoon, Parcharee ; Xu, Mengshu ; Shunatona, Hunter P. ; Shibuya, Grant M. ; Pookot, Deepa ; Maung, Jack ; Wustrow, David J.

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Microsatellite Instability cancer	Preclinical	United States	Rapt Therapeutics, Inc.	29 Oct 2022

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