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 PMID: 36127295

ADC Targets in Oncology

2026-04-10

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

J Med Chem. 2022 Oct 13;65(19):12895-12924. doi: 10.1021/acs.jmedchem.2c00736.

Jeffrey J Jackson ¹ , Grant M Shibuya ¹ , Buvana Ravishankar ¹ , Lavanya Adusumilli ¹ , Delia Bradford ¹ , Dirk G Brockstedt ¹ , Cyril Bucher ¹ , Minna Bui ¹ , Cynthia Cho ¹ , Christoph Colas ¹ , Gene Cutler ¹ , Adrian Dukes ¹ , Xinping Han ¹ , Dennis X Hu ¹ , Scott Jacobson ¹ , Paul D Kassner ¹ , George E Katibah ¹ , Michelle Yoo Min Ko ¹ , Urvi Kolhatkar ¹ , Paul R Leger ¹ , Anqi Ma ¹ , Lisa Marshall ¹ , Jack Maung ¹ , Andrew A Ng ¹ , Akinori Okano ¹ , Deepa Pookot ¹ , Daniel Poon ¹ , Chandru Ramana ¹ , Maureen K Reilly ¹ , Omar Robles ¹ , Jacob B Schwarz ¹ , Anton A Shakhmin ¹ , Hunter P Shunatona ¹ , Raashi Sreenivasan ¹ , Parcharee Tivitmahaisoon ¹ , Mengshu Xu ¹ , Thant Zaw ¹ , David J Wustrow ¹ , Mikhail Zibinsky ¹

Affiliations

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.