Discover how pharmacological targeting of HRI kinase offers new hope for patients with myelodysplastic syndromes with ringed sideroblasts and sickle cell disease
Imagine your body constantly producing red blood cells that are destined to fail—cells that develop but cannot mature properly, leaving you severely anemic and dependent on lifelong blood transfusions.
This is the reality for patients with myelodysplastic syndromes with ringed sideroblasts (MDS-RS)—a condition where the bone marrow fails to produce healthy red blood cells.
For those with sickle cell disease (SCD), the problem is defective red blood cell function, where cells sickle under stress, causing pain and organ damage.
HRI, scientifically known as eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1), is part of what biologists call the integrated stress response (ISR)—a critical survival pathway that cells activate when facing various threats 1 .
This kinase functions as a molecular sensor that detects heme deficiency—heme being the iron-containing compound that gives blood its red color and enables oxygen transport. When heme levels drop, HRI activates and phosphorylates a key protein called eIF2α, essentially putting the brakes on general protein production while selectively allowing protective proteins to be synthesized 5 .
In MDS-RS, the problem begins with mutations in the SF3B1 gene, which functions as a master conductor of RNA splicing. SF3B1 mutations cause mis-splicing of genes involved in heme transport, trapping heme in mitochondria instead of making it available for hemoglobin production 1 6 .
The erythroblasts sense this heme deficiency and activate HRI, which arrests their maturation at the final stage of development 6 .
In sickle cell disease, the primary issue is a structural abnormality in hemoglobin that causes red blood cells to sickle under stress.
Researchers discovered that HRI activation suppresses fetal hemoglobin production—the form of hemoglobin that naturally occurs in infants and effectively resists sickling 1 .
| Feature | MDS-RS | Sickle Cell Disease |
|---|---|---|
| Primary defect | Dysplastic erythropoiesis | Hemoglobin polymerization |
| Genetic basis | Acquired SF3B1 mutations | Inherited hemoglobin beta-chain mutation |
| HRI role | Arrests erythroid maturation | Suppresses fetal hemoglobin |
| Characteristic feature | Ringed sideroblasts in bone marrow | Sickled red blood cells in circulation |
| Current treatments | Erythropoiesis-stimulating agents, transfusions | Hydroxyurea, pain management, transfusions |
The turning point came when researchers asked: What if we could chemically interrupt the pathological HRI signaling that disrupts red blood cell production? This led to a collaboration between academic researchers and MD Anderson's Institute of Applied Cancer Science to develop selective HRI inhibitors 1 .
Using virtual screening and structural insights from other kinase inhibitor programs, the team designed and synthesized more than 200 diverse compounds. They established a robust screening platform including biochemical and cellular assays to monitor HRI's phosphorylation of eIF2α 1 .
The result was two promising compounds: IACS-18148 and IACS-77717, which inhibited HRI kinase activity with exceptional potency and selectivity. These compounds showed half-maximal inhibitory concentration (IC50) values of 7.2 and 1.3 nM respectively, with 140- to 650-fold selectivity for HRI over other ISR family members 1 .
IC50 Value
IC50 Value
One compelling study published in Blood Cancer Discovery provides a perfect example of how researchers validated HRI inhibition as a therapeutic strategy 6 . The investigation employed:
Of lineage-negative CD34+ hematopoietic stem and progenitor cells (HSPCs) isolated from bone marrow of five untreated SF3B1-mutant MDS-RS patients and two age-matched healthy donors.
Using primary patient samples to test whether targeting the HRI pathway could rescue erythroid differentiation.
Of HRI in patient-derived erythroblasts to confirm that the effects were specifically due to HRI inhibition.
In MDS-RS samples, treatment with IACS-18148 for five days resulted in significantly higher co-expression of CD71 and CD235a—markers of terminal erythroid differentiation—compared to vehicle-treated cells 1 .
In SCD patient-derived erythroblasts, IACS-18148 and IACS-77717 decreased BCL11A while increasing HBG1/2 expression (the genes encoding fetal hemoglobin) 1 .
| Experimental Model | Treatment | Key Results | Significance |
|---|---|---|---|
| SF3B1-mutant MDS-RS erythroblasts | IACS-18148 for 5 days | ↑ CD71/CD235a co-expression (80.3% vs 50.9%) | Rescued terminal erythroid differentiation |
| SCD patient-derived erythroblasts | IACS-18148 for 13 days | ↓ BCL11A (1.6-fold); ↑ HBG1/2 (3.2-fold) | Increased fetal hemoglobin production |
| SCD patient-derived erythroblasts | IACS-77717 for 13 days | ↓ BCL11A (1.2-fold); ↑ HBG1/2 (4.6-fold) | Increased fetal hemoglobin production |
| SF3B1K700E knock-in cells | IACS-18148 or IACS-77717 (30 min) | Inhibited eIF2α phosphorylation (IC50=88/46 nM) | Confirmed target engagement |
The groundbreaking discoveries in HRI research were made possible by sophisticated research tools and methodologies.
| Research Tool | Function/Application | Key Insights Generated |
|---|---|---|
| scRNA-seq | Profiling transcriptomic states of individual cells | Identified EIF2AK1 pathway activation in SF3B1-mutant erythroblasts 6 |
| scATAC-seq | Mapping chromatin accessibility landscape | Revealed erythroid bias at epigenetic level in SF3B1-mutant HSPCs 6 |
| CRISPR/Cas9 gene editing | Selective gene knockout/in | Validated HRI as critical dependency in SF3B1-mutant erythropoiesis 1 |
| Phospho-specific antibodies | Detecting phosphorylated eIF2α | Confirmed HRI pathway activation and inhibitor engagement 1 |
| Flow cytometry antibodies | Detecting CD71, CD235a, CD34 | Quantified erythroid differentiation stages 1 6 |
| Virtual screening libraries | Identifying novel inhibitor scaffolds | Discovered IACS-18148 and IACS-77717 lead compounds 1 |
For MDS-RS patients, who currently face limited options beyond erythropoiesis-stimulating agents and regular transfusions, HRI inhibitors could potentially restore their ability to produce functional red blood cells, eliminating transfusion dependency and its associated complications like iron overload 2 .
Potential game-changer for quality of life
For sickle cell disease patients, HRI inhibitors could offer an oral alternative or complement to existing therapies like hydroxyurea. The magnitude of fetal hemoglobin induction observed in preclinical studies—3.2 to 4.6-fold increases—suggests potentially meaningful clinical benefits 1 7 .
Natural defense against sickling
The success in targeting HRI demonstrates the therapeutic potential of modulating the integrated stress response—a pathway implicated in numerous conditions including neurodegeneration, metabolic disorders, and cancer 4 .
The drug development approaches used, particularly the virtual screening and structural design strategies, may serve as templates for targeting other challenging kinases.
The journey from basic scientific discovery to therapeutic application is often long and winding, but the story of HRI inhibition exemplifies how deep molecular understanding can reveal unexpected therapeutic opportunities.
By recognizing the common role of HRI pathway activation in seemingly disparate conditions, researchers have opened the door to novel treatments.
HRI inhibitors address underlying pathological mechanisms rather than just symptoms.
Potential to fundamentally alter disease course for patients facing lifelong disability.
The days of simply managing the symptoms of these complex blood disorders may soon be behind us, thanks to a dedicated focus on the intricate dance of molecules within our cells and the creative determination to intervene when that dance goes awry.