Abstract 6874: Bkt300, a novel small molecule targeting the protein regulator of cytokinesis 1 pathway in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) remains a major cause of cancer mortality worldwide, largely due to its high recurrence rate and chemoresistance. The microtubule-associated protein regulator of cytokinesis 1 (PRC1) has been implicated in HCC progression, associated with poor prognosis, enhanced cancer proliferation, stemness, metastasis, and chemoresistance. PRC1 functions as an oncogenic driver, particularly in HCC cases with elevated expression, where it promotes Wnt signaling and the expression of genes linked to early recurrence. BKT300, a novel targeted anti-cancer agent, was found to inhibit PRC1, offering a potential treatment option for advanced, difficult-to-treat cancers that express high levels of PRC1, such as HCC. This study investigated the effects of BKT300 on HCC cell migration and survival pathways. BKT300 selectively inhibited HCC cell migration, induced G2/M cell cycle arrest, and triggered mitotic catastrophe and apoptosis through the caspase 3 pathway. BKT300 targeted PRC1 by arresting it in a phosphorylated state at T481, concurrently downregulating CDC25C and upregulating p21. siRNA-mediated suppression of PRC1 in HCC cells prevented the activity of BKT300, indicating that BKT300’s efficacy is dependent on PRC1 expression. Direct binding of BKT300 to PRC1 was further confirmed through multiple assays. In vivo studies in two HCC mouse models demonstrated significant tumor growth inhibition and tumor regression, underscoring the therapeutic promise of BKT300 for HCC. Overall, BKT300 presents a novel approach to tackling HCC by directly targeting PRC1, potentially improving outcomes in HCC cases with high PRC1 expression and resistance to conventional therapies. Citation Format: Amnon Peled, Lika Gamaev, Hanna Wald, Rakefet Rosenfeld, Orly Eizenberg, Arnon Aharon, Michal Abraham. Bkt300, a novel small molecule targeting the protein regulator of cytokinesis 1 pathway in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6874.