Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy

Journal Article (Journal Article)

PBX1 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. 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.

Full Text

Duke Authors

Cited Authors

  • Shen, YA; Jung, J; Shimberg, GD; Hsu, FC; Rahmanto, YS; Gaillard, SL; Hong, J; Bosch, J; Shih, IM; Chuang, CM; Wang, TL

Published Date

  • November 19, 2021

Published In

Volume / Issue

  • 24 / 11

Electronic International Standard Serial Number (EISSN)

  • 2589-0042

Digital Object Identifier (DOI)

  • 10.1016/j.isci.2021.103297

Citation Source

  • Scopus