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

Yao An Shen, Jin Jung, Geoffrey D. Shimberg, Fang Chi Hsu, Yohan Suryo Rahmanto, Stephanie L. Gaillard, Jiaxin Hong, Jürgen Bosch, Ie Ming Shih, Chi Mu Chuang, Tian Li Wang

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number103297
JournaliScience
Volume24
Issue number11
DOIs
StatePublished - Nov 19 2021

Keywords

  • Cancer
  • Chemistry

ASJC Scopus subject areas

  • General

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