DOCK1 inhibitor Box5 (TFA) suppresses proliferation of AML cell lines and prolongs survival in AML xenograft models.

The Dedicator of Cytokinesis1 (DOCK1) has been implicated in solid tumors; however, its precise role and therapeutic potential in acute myeloid leukemia (AML) remain largely unexplored. Here we investigated the prognostic significance and functional roles of DOCK1 in AML. A novel small-molecule inhibitor targeting DOCK1 was identified and characterized. Our findings revealed that DOCK1 expression was significantly elevated in AML patients and predicted poor overall survival, serving as potentially independent prognostic factor. DOCK1 knockdown inhibited AML cell viability, induced apoptosis and S-phase cell cycle arrest, and impaired colony formation. In xenograft models, DOCK1 depletion significantly reduced leukemic burden and prolonged survival. From a targeted screen, we identified Box5 (TFA) as a potent DOCK1 inhibitor, which binds directly to DOCK1 and effectively suppresses AML cell viability and colony formation in vitro. Box5 (TFA) treatment in vivo mirrored the genetic knockdown, significantly reducing tumor infiltration and extending survival in AML xenograft models. Our study establishes DOCK1 as a candidate oncoprotein and a potentially independent prognostic biomarker in AML. These findings provide a rationale for targeting DOCK1 and support the development of Box5 (TFA) as a promising therapeutic strategy for AML.