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

Summary: 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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Chemistry Cancer Science Q
Acceso en línea:	https://doaj.org/article/8619e16c5d294c30acce63292715bdfb
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spelling	oai:doaj.org-article:8619e16c5d294c30acce63292715bdfb2021-11-20T05:09:35ZDevelopment of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy2589-004210.1016/j.isci.2021.103297https://doaj.org/article/8619e16c5d294c30acce63292715bdfb2021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221012669https://doaj.org/toc/2589-0042Summary: 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.Yao-An ShenJin JungGeoffrey D. ShimbergFang-Chi HsuYohan Suryo RahmantoStephanie L. GaillardJiaxin HongJürgen BoschIe-Ming ShihChi-Mu ChuangTian-Li WangElsevierarticleChemistryCancerScienceQENiScience, Vol 24, Iss 11, Pp 103297- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Chemistry Cancer Science Q
spellingShingle	Chemistry Cancer Science Q 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 Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy
description	Summary: 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.
format	article
author	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
author_facet	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
author_sort	Yao-An Shen
title	Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy
title_short	Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy
title_full	Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy
title_fullStr	Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy
title_full_unstemmed	Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy
title_sort	development of small molecule inhibitors targeting pbx1 transcription signaling as a novel cancer therapeutic strategy
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/8619e16c5d294c30acce63292715bdfb
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Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy

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