Abstract

Erythropoietin (EPO) or its biosimilar variants have been widely used to treat anemia caused by chronic kidney disease and cancer. This treatment is effective but has its drawbacks, including high cost, inconvenient intravenous administration, and occasional serious side effects, including the formation of antibodies against EPO. There is an ongoing search for a small molecule replacement for EPO that could trigger erythropoiesis efficiently but would be cheaper to produce and can be delivered orally. Therefore, we have developed a high-throughput assay for the sensitive detection of hemoglobin production in hematopoietic cells and screened a library of small molecules for potential inducers of erythropoiesis. We identified several kinase inhibitors, including established drugs, that could induce differentiation of primary erythroid progenitors into erythrocytes in the absence of EPO. To elucidate the mechanism of action, we combined proteomic experiments with transcriptomic and chromatin accessibility studies.