Shen Yao-An, Jung Jin, Shimberg Geoffrey D, Hsu Fang-Chi, Rahmanto Yohan Suryo, Gaillard Stephanie L, Hong Jiaxin, Bosch Jürgen, Shih Ie-Ming, Chuang Chi-Mu, Wang Tian-Li
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.
iScience. 2021 Oct 15;24(11):103297. doi: 10.1016/j.isci.2021.103297. eCollection 2021 Nov 19.
PBX1 is a transcription factor involved in diverse cellular functions including organ development, stem cell renewal, and tumorigenesis. 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.
PBX1是一种转录因子，参与多种细胞功能，包括器官发育、干细胞更新和肿瘤发生。它定位于1q23.3染色体，这是一个经常扩增的染色体区域，并且在许多人类恶性肿瘤中过表达。具有升高的PBX1信号的癌细胞特别容易受到PBX1缺失的影响。我们设计了一系列能够与PBX1及其同源DNA靶序列之间的界面结合的小分子化合物。其中，T417被发现是一种先导化合物。在基于细胞的试验中，T417显著抑制了表达高水平PBX1的癌细胞的自我更新和增殖。T417还使铂耐药卵巢肿瘤对卡铂重新敏感。T417可能由于健康组织中较低的PBX1表达水平而不影响它们。因此，靶向PBX-DNA界面可能是治疗依赖PBX1生存的人类肿瘤的一种有前景的策略。
