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
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.
