Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy
Yao Shen, Jin Gyoung Jung, Geoffrey D. Shimberg, Fang‐Chi Hsu, Yohan Suryo Rahmanto, Stéphanie Gaillard, Jiaxin Hong, Jürgen Bosch, Ie‐Ming Shih, Chi-Mu Chuang, Tian‐Li Wang
Abstract
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.