H11 is a first-in-class bifunctional HDAC and autophagy inhibitor with potent antileukemic activity

Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy characterized by the accumulation of immature myeloid blasts that disrupt hematopoiesis. Although initial remissions can be achieved with standard chemotherapy, relapse is frequent and durable responses remain uncommon. This underscores the need for new therapeutic strategies that can overcome established resistance mechanisms. Disruption of epigenetic homeostasis is a common feature of AML pathogenesis and offers an opportunity for targeted therapy. Histone deacetylase (HDAC) inhibitors are one class of agents that induce epigenetic reprogramming and have previously demonstrated antileukemic activity. However, their efficacy is blunted by the activation of cytoprotective autophagy. Simultaneous blockade of HDAC activity and autophagic flux therefore represents a rational approach to enhance therapeutic benefit. To address this, we developed H11, a first-in-class bifunctional small molecule engineered to concurrently inhibit HDACs and suppress autophagy. H11 potently reduced viability and triggered apoptosis across genetically diverse AML models and primary AML specimens from patients including those with adverse features such as FLT3-ITD and loss of p53 function. H11 retained potent activity in models resistant to frontline therapies, indicating its potential to overcome both epigenetic and lysosomal-mediated resistance mechanisms. Importantly, H11 demonstrated strong therapeutic selectivity with very limited effects against normal CD34+ bone marrow progenitors. Mechanistic studies demonstrated robust HDAC inhibition, evidenced by increased global histone acetylation, coupled with impaired autophagic degradation, reflected by p62 accumulation, lysosomal deacidification, and blocked autophagic flux. H11 treatment also decreased the expression of the oncogenic transcription factor c-Myc and increased CDKN1A (p21), consistent with epigenetic reprogramming and disruption of AML survival circuitry. Because epigenetic dysregulation is a hallmark of AML, we next evaluated H11 in combination with the FDA-approved hypomethylating agent azacitidine (AZA). The H11-AZA combination produced strong synergy, markedly enhancing cytotoxicity across multiple AML cell lines and significantly extending overall survival in an orthotopic FLT3-ITD+ mouse xenograft model of AML. Together, these findings establish H11 as a first-in-class dual HDAC-autophagy inhibitor that integrates epigenetic modulation with autophagy suppression to promote apoptosis and disrupt adaptive AML survival pathways. This coordinated mechanism of action highlights H11 as a promising next-generation therapeutic with strong potential to improve clinical outcomes in patients with AML.