Developing an inhibitor of EIF2AK1 to overcome ineffective erythropoiesis in myelodysplastic syndromes with ringed sideroblasts

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ABSTRACT Mutations in the splicing factor SF3B1 (SF3B1MT), which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of MDS-RS, an MDS subtype characterized by the accumulation of ringed sideroblasts (RS) in the bone marrow. SF3B1MT are found in different hematopoietic cell types but preferentially deregulate erythroid progenitors. Although MDS-RS has a low propensity for leukemic transformation, most patients with MDS-RS have severe anemia and depend on regular blood transfusions despite the increased risk of iron overload and other adverse outcomes. The only agent approved for the treatment of transfusion-dependent MDS-RS patients who are ineligible for or have no response to erythropoiesis-stimulating agents is luspatercept, an inhibitor of TGFβ signaling. However, luspatercept has a response rate of less than 40%, which underscores the need for alternative treatment options that can alleviate impaired erythroid differentiation in these patients. In our previous study, we identified the EIF2AK1 response to heme deficiency as a potential driver of the SF3B1MT-induced arrest of erythroid differentiation. We therefore hypothesize that pharmacologically inhibiting EIF2AK1 activation overcomes ineffective erythropoiesis in patients with SF3B1-mutant MDS-RS. To test this hypothesis, we will pursue the specific aim of developing a small-molecule inhibitor of EIF2AK1 activity for proof-of-concept studies in SF3B1-mutant MDS samples. The findings of this aim will provide a direct line of sight to future compounds suitable for clinical development. We have partnered with the Institute of Applied Cancer Science at MD Anderson Cancer Center to develop small molecules targeting the EIF2AK1 pathway in MDS-RS. Our multidisciplinary team has already identified several EIF2AK1 inhibitors that have low nanomolar potency, are highly permeable and free of efflux, and have good selectivity relative to other members of the EIF2AK family of protein kinases. In the proposed work, we will functionally validate these candidates using cellular assays (employing primary cells, induced pluripotent stem cells, and genetically engineered cell lines) that we have developed over the last 3 years. If successful, this study will enable the development of the first inhibitor of EIF2AK1 activity. The proposed work has implications for the development of therapies to achieve long-lasting hematological responses in transfusion-dependent MDS-RS patients. Given that EIF2AK1 inhibition is one of the most promising therapeutic approaches for sickle cell anemia to date, the results of our work may have a broad spectrum of application.