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

iScience (Nov 2021)

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

Affiliations

Yao-An Shen: Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB2, Room 306, Baltimore, MD 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Jin Jung: Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB2, Room 306, Baltimore, MD 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Geoffrey D. Shimberg: Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB2, Room 306, Baltimore, MD 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Fang-Chi Hsu: Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB2, Room 306, Baltimore, MD 21231, USA
Yohan Suryo Rahmanto: Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB2, Room 306, Baltimore, MD 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Stephanie L. Gaillard: Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB2, Room 306, Baltimore, MD 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Jiaxin Hong: Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB2, Room 306, Baltimore, MD 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Jürgen Bosch: Division of Pulmonology and Allergy/Immunology, Case Western Reserve University, Cleveland, OH, USA; InterRayBio, LLC, Baltimore MD, USA; Corresponding author
Ie-Ming Shih: Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB2, Room 306, Baltimore, MD 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Corresponding author
Chi-Mu Chuang: Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Midwifery and Women Health Care, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan; Corresponding author
Tian-Li Wang: Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB2, Room 306, Baltimore, MD 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Corresponding author

Journal volume & issue: Vol. 24, no. 11
p. 103297

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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