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Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single
Jeffrey J Jackson1, Grant M Shibuya1, Buvana Ravishankar1
1RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California94080, United States.
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.
Insights
A novel compound targeting General control nonderepressible 2 (GCN2) kinase effectively inhibits tumor growth and restores T cell function. This GCN2 inhibitor shows promise in cancer immunotherapy by overcoming immune suppression in the tumor microenvironment.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor implicated in tumor immune escape.
- Targeting GCN2 signaling is a potential strategy to enhance anti-tumor immunity.
Purpose of the Study:
- To discover and characterize potent and selective GCN2 inhibitors.
- To evaluate the efficacy of a novel GCN2 inhibitor, compound 39, in preclinical cancer models.
Main Methods:
- Discovery of cell-potent GCN2 inhibitors with high selectivity against related kinases (HRI, PKR, PERK).
- Pharmacokinetic (PK) profiling and in vivo target engagement studies of compound 39 in mice.
- Assessment of compound 39's effect on myeloid-derived suppressor cell (MDSC)-mediated T cell suppression and proliferation.
- Evaluation of compound 39's anti-tumor efficacy as a single agent and in combination with anti-VEGFR therapy in the LL2 syngeneic mouse model.
Main Results:
- Compound 39 demonstrated potent GCN2 engagement (≥80%) in mice at 15 mg/kg BID.
- Compound 39 alleviated MDSC-related T cell suppression and restored T cell proliferation.
- Compound 39 achieved significant tumor growth inhibition (TGI) as a monotherapy in the LL2 model.
- Combination therapy with compound 39 and anti-VEGFR enhanced TGI, indicating synergistic effects.
Conclusions:
- Novel, selective GCN2 inhibitors were discovered, with compound 39 showing promising preclinical anti-tumor activity.
- Compound 39 effectively modulates the tumor microenvironment by reducing immune suppression and restoring T cell function.
- Compound 39 represents a potential therapeutic agent for cancer, particularly when combined with other immunotherapies like anti-VEGFR.
