Development of Small Molecule Inhibitors Targeting PBX1 Transcription Signaling as a Novel Cancer Therapeutic Strategy

PBX1 (pre-B cell leukemia transcription factor 1) is a transcription factor involved in diverse cellular functions including organ development, stem cell renewal, and tumorigenesis. PBX1 is localized at chr1q23.3, a frequently amplified chromosomal region, and it is overexpressed in many human malignancies including breast, lung, melanoma, and ovarian carcinomas. 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 and identified a lead compound, T417, which efficiently hindered the formation of the PBX1 transcriptional complex and affected the transcription of PBX1 target genes. In cell-based assays, T417 significantly suppressed long-term self-renewal and proliferation of cancer cells expressing high levels of PBX1 but not of those expressing low levels of PBX1. T417 also re-sensitized platinum-resistant ovarian tumor cells to carboplatin and produced synergistic anti-tumorigenic effects in vivo in combination with carboplatin. Normal tissues were spared, likely due to the lower PBX1 expression levels. Since PBX1 functions as a molecular hub in developing cancer recurrence and treatment resistance, our data highlight the potential of targeting the PBX-DNA interface as a therapeutic strategy for patients whose tumors rely on PBX1 activation for survival.