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

  • iScience. 2021 Oct 15;24(11):103297. doi: 10.1016/j.isci.2021.103297.
Yao-An Shen  1  2  3 ,  Jin Jung  1  2 ,  Geoffrey D Shimberg  1  2 ,  Fang-Chi Hsu  1 ,  Yohan Suryo Rahmanto  1  2 ,  Stephanie L Gaillard  1  2 ,  Jiaxin Hong  1  2 ,  Jürgen Bosch  4  5 ,  Ie-Ming Shih  1  2 ,  Chi-Mu Chuang  6  7  8 ,  Tian-Li Wang  1  2
Affiliations
  • 1. Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB2, Room 306, Baltimore, MD 21231, USA.
  • 2. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 3. Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 4. Division of Pulmonology and Allergy/Immunology, Case Western Reserve University, Cleveland, OH, USA.
  • 5. InterRayBio, LLC, Baltimore MD, USA.
  • 6. Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
  • 7. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.
  • 8. Department of Midwifery and Women Health Care, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.
PMID: 34816098 DOI: 10.1016/j.isci.2021.103297
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.

Keywords
Cancer; Chemistry.
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