BKT300: A Novel Anti-Leukemic Small Molecule Targeting the Protein Regulator of Cytokinesis 1 (PRC1) Pathway

Protein regulator of cytokinesis 1 (PRC1) is frequently overexpressed in various cancers and is associated with poor prognosis. BKT300 is a small molecule shown to selectively inhibit leukemic cell migration and survival by targeting the PRC1 pathways. The current work aimed to examine the role of PRC1 in acute myeloid leukemia (AML) and to assess the impact of BKT300, a small molecule PRC1 inhibitor, on AML cell viability and tumor growth in mouse xenograft AML models. BKT300 directly bound PRC1, resulting in disrupted actin and microtubule formation, G2/M cell cycle arrest, mitotic catastrophe and apoptosis via the caspase-3 pathway in AML cells. BKT300 inhibited PRC1 dephosphorylation at T481, downregulated CDC25C and upregulated p21, effectively halting the cell cycle and inhibiting leukemic cell proliferation while sparing normal cells. PRC1 was found to be overexpressed in AML patients and cell lines, with high levels associated with reduced overall patient survival. In addition, PRC1 expression levels correlated with BKT300 efficacy. BKT300 treatment led to 98% of tumor growth inhibition and 89.4% of tumor regression in mouse xenograft AML models, without notable impacts on normal hematopoiesis or biochemistry, even at high doses. As a first-in-class targeted therapy, BKT300 presents a promising new treatment option for advanced AML.