摘要：SummaryPBX1 is a transcription factor involved in diverse cellular functions including organ development, stem cell renewal, and tumorigenesis.PBX1is localized at chr1q23.3, a frequently amplified chromosomal region, and it is overexpressed in many human malignancies. Cancer cells with elevated PBX1 signaling are particularly vulnerable to PBX1 withdrawal. We designed a series of small molecule compounds capable of docking to the interface between PBX1 and its cognate DNA target sequence. Among them, T417 is found to be a lead compound. In cell-based assays, T417 significantly suppressed self-renewal and proliferation of cancer cells expressing high levels of PBX1. T417 also re-sensitized platinum-resistant ovarian tumors to carboplatin. T417 did not affect healthy tissues likely due to their lower PBX1 expression levels. Therefore, targeting PBX-DNA interface can be a promising strategy for treating human tumors reliant on PBX1 for survival.Graphical abstractDisplay OmittedHighlights•Developing small molecular compounds to interfere with PBX1 protein and DNA interaction•Lead compound, T417, is potent in affecting PBX1 transcription•T417 displays lowin vivotoxicity and satisfactoryin vivoanti-tumor potencyChemistry; Cancer
