ArticleClinical cancer research : an official journal of the American Association for Cancer Research2026
A Novel Potent and Selective GCN2 Inhibitor, APL-4098, Has Antileukemic Activity through Dysregulation of Mitochondrial Function.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- ATF4: Orchestrating Cellular Stress Adaptation, Metabolism, and Immune Regulation in Health and Disease.International journal of molecular sciences · 2026Review
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10 authors.
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Abstract
purposeGCN2, one of the four kinases that activate the integrated stress response to maintain proteostasis, has been shown to support cancer cell growth and survival in multiple preclinical cancer models. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor prognosis and high relapse rates that is marked by a dependency on finely tuned proteostasis. In this study, we investigate the antileukemic potential of a new small-molecule GCN2 inhibitor, APL-4098. EXPERIMENTAL
designSelectivity and potency of APL-4098 were assessed using biochemical and cell-based assays. Antileukemic effects were evaluated ex vivo in primary patient-derived AML and in vivo using cell line-derived (CDX) and patient-derived xenograft (PDX) models. Synergy of APL-4098 and venetoclax was examined in the PDX model. RNA sequencing and metabolic assays were used to explore APL-4098 mechanism of action.
resultsAPL-4098 exhibited nanomolar-range potency against and high selectivity for GCN2. APL-4098 showed strong antiproliferative activity ex vivo across two independent cohorts of cells from patients with primary AML, including cytotoxic effects on the leukemia stem cells (LSC) and in vivo, achieving 98% tumor growth inhibition in an AML CDX. In a PDX, APL-4098 preferentially depleted the LSC-enriched compartment and, in combination with venetoclax, reduced leukemia burden by more than 98%. Transcriptomic and metabolic analyses revealed that APL-4098 compromises mitochondrial function and elicits the mitochondrial unfolded protein response.
conclusionsAPL-4098 is a novel, potent, and selective GCN2 inhibitor with strong preclinical efficacy against AML cells, including LSC. Our findings support APL-4098 as a promising candidate for AML treatment.
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