Stromal antigen 1 and 2 (STAG1 and STAG2) are two mutually exclusive components of the cohesin complex that is crucial for centromeric and telomeric cohesion. Beyond its structural role, STAG2 also plays a pivotal role in homologous recombination (HR) repair and has emerged as a promising therapeutic target in cancer treatment. Here, we employed a fluorescence polarization (FP)-based high-throughput screening and identified KPT-6566 as a dual inhibitor of STAG1 and STAG2. Biochemical and biophysical analyses demonstrated that KPT-6566 directly binds to STAG1 and STAG2, disrupting their interactions with SCC1 and double-stranded DNA. A metaphase chromosome spread assay showed that KPT-6566 causes premature chromosome separation and induces chromosome damages in HeLa cells. Furthermore, KPT-6566 also impairs DNA damage repair, leading to the accumulation of double-strand breaks and cell apoptosis. Finally, KPT-6566 can sensitize HeLa and HepG2 cells to PARP inhibitor Olaparib and the NHEJ inhibitor UMI-77, exhibiting a synergistic effect in suppressing cell proliferation. Our findings highlight the potential of STAG1/2 as promising therapeutic targets in cancer treatment, particularly when they are targeted in combination with other DNA damage response inhibitors.

01 Jul 2024·European Journal of Pharmacology

Discovery of UMI-77 as a novel Ku70/80 inhibitor sensitizing cancer cells to DNA damaging agents in vitro and in vivo

Article

Author: Lin, Zhonghui ; Chen, Changkun ; Chen, Xuening ; Liu, Jianyong ; Luo, Chengmiao

The emergence of chemoresistance poses a significant challenge to the efficacy of DNA-damaging agents in cancer treatment, in part due to the inherent DNA repair capabilities of cancer cells. The Ku70/80 protein complex (Ku) plays a central role in double-strand breaks (DSBs) repair through the classical non-homologous end joining (c-NHEJ) pathway, and has proven to be one of the most promising drug target for cancer treatment when combined with radiotherapy or chemotherapy. In this study, we conducted a high-throughput screening of small-molecule inhibitors targeting the Ku complex by using a fluorescence polarization-based DNA binding assay. From a library of 11,745 small molecules, UMI-77 was identified as a potent Ku inhibitor, with an IC₅₀ value of 2.3 μM. Surface plasmon resonance and molecular docking analyses revealed that UMI-77 directly bound the inner side of Ku ring, thereby disrupting Ku binding with DNA. In addition, UMI-77 also displayed potent inhibition against MUS81-EME1, a key player in homologous recombination (HR), demonstrating its potential for blocking both NHEJ- and HR-mediated DSB repair pathways. Further cell-based studies showed that UMI-77 could impair bleomycin-induced DNA damage repair, and significantly sensitized multiple cancer cell lines to the DNA-damaging agents. Finally, in a mouse xenograft tumor model, UMI-77 significantly enhanced the chemotherapeutic efficacy of etoposide with little adverse physiological effects. Our work offers a new avenue to combat chemoresistance in cancer treatment, and suggests that UMI-77 could be further developed as a promising candidate in cancer treatment.

01 Jun 2024·Aging Cell

Mitophagy defect mediates the aging‐associated hallmarks in Hutchinson–Gilford progeria syndrome

Article

Author: Sun, Yingying ; Zhang, Jin ; Xu, Le ; Wang, Gang ; Xia, Hongguang ; Fu, Xudong ; Wang, Jingjing ; Cao, Zhongkai ; Li, Yi ; Xu, Yuyan ; Cen, Xufeng ; Mao, Jianhua ; Liu, Zhihong ; Hu, Lidan ; Shen, Ning ; Jia, Shunze

AbstractHutchinson–Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging‐related phenotypes, making it a disease model for aging. The cellular machinery mediating age‐associated phenotypes in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS. In this study, we showed that mitophagy defects impaired mitochondrial function and contributed to cellular markers associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS‐MSCs). Mechanistically, we discovered that mitophagy affected the aging‐associated phenotypes of HGPS‐MSCs by inhibiting the STING‐NF‐ĸB pathway and the downstream transcription of senescence‐associated secretory phenotypes (SASPs). Furthermore, by utilizing UMI‐77, an effective mitophagy inducer, we showed that mitophagy induction alleviated aging‐associated phenotypes in HGPS and naturally aged mice. Collectively, our results uncovered that mitophagy defects mediated the aging‐associated markers in HGPS, highlighted the function of mitochondrial homeostasis in HGPS progression, and suggested mitophagy as an intervention target for HGPS and aging.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	The University of Michigan-Dearborn	-
Neoplasms	Preclinical	US	Barbara Ann Karmanos Cancer Institute	-

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