A first-in-class multimodal organomercury compound demonstrates preferential blast reduction with improved hematopoietic and immune health in ALL

Abstract

Acute leukemia treatment requires effective blast reduction while improving hematopoietic and immune health. As reported previously, we developed a structurally distinct organomercury derivative of curcumin, -Mercurin, having improved aqueous solubility and intravenous applicability. Here we comprehensively evaluated therapeutic efficacy, pharmacological response, systemic toxicity, blood Hg pharmacokinetics (PK), Hg biodistribution and elimination profile for -Mercurin in a N-nitroso-N-ethylurea (ENU)-induced autochthonous Acute lymphoblastic leukemia (ALL) rat model, comparing with clinical standard cytarabine. Results showed recovery in body-weight, along with longer time-to-humane-endpoint from 13 to 39 days. Treatment successfully reduced immature blast count, while promoting erythroid, myeloid, and megakaryocytic compartments and improving immune mediators across peripheral blood, bone marrow, thymus, spleen, and lymph nodes. Histopathology showed reduced leukemic infiltration with preservation of major organ architecture, while cytarabine produced evident myelosuppression, neurotoxicity, and cardiotoxicity. PK study showed blood Hg reached Tmax at 15 min, followed by urinary and fecal elimination with residual retention in kidney tissue and no detectable Hg in brain. Collectively, -Mercurin demonstrated a promising multimodal therapeutic index, combining cytoreductive activity with improvement in hematopoietic and immune health, along with favorable safety profile for future ALL therapy.