Author: Wang, Dawei ; Yang, Peng ; Hou, Yi ; Min, Wenjian ; Wang, Xiao ; Wang, Liping ; Ji, Jiaying ; Shen, Hao ; Chen, Yuanyuan ; Hu, Lingrong ; Zhu, Yasheng ; Ding, Jiayu

MTDH-SND1 protein-protein interaction (PPI) plays an important role in the initiation and development of tumors, and it is a target for the treatment of breast cancer. In this study, we identified and synthesized a series of novel small-molecule inhibitors of MTDH-SND1 PPI. The representative compound C19 showed potent activity against MTDH-SND1 PPI with an IC₅₀ of 487 ± 99 nM and tight binding to the SND1-purified protein with a K_d value of 279 ± 17 nM. Compound C19 significantly degraded SND1 and downregulated downstream at the protein level. Further biological evaluations suggested that compound C19 exhibited potent activity against the proliferation of breast cancer MCF-7 cells with an IC₅₀ value of 626 ± 27 nM, significantly inhibited invasion and migration, and induced cell apoptosis. In addition, compound C19 exhibited promising tumor growth inhibition in the xenograft model. Our study provides a potential candidate targeting MTDH-SND1 PPI for the treatment of breast cancer.

27 Oct 2017·Oncotarget

Targeting cyclophilin-D by compound 19 protects neuronal cells from oxygen glucose deprivation/re-oxygenation

Article

Author: Yang, Haikou ; Yan, Ming ; Sun, Jian ; Zhou, Jing ; Cui, Enhui ; Zheng, Jinyu ; Tang, De-Rong ; Li, Mao

Oxygen and glucose deprivation (OGD) with re-oxygenation (OGDR) is applied to neuronal cells to mimic ischemia-reperfusion injuries. Activation of cyclophilin D (Cyp-D)-dependent programmed necrosis pathway mediates OGDR-induced neuronal cell damages. Here, we tested the potential effect of Compound 19 (C19), a novel Cyp-D inhibitor, in this process. In both established neuronal cell lines (Neuro-2a and NB41A3 cells) and the primary murine CA1 hippocampal neurons, pretreatment with C19 largely attenuated OGDR-induced cell viability reduction and cell death. Significantly, C19 was ineffective in Cyp-D-silenced Neuro-2a cells. OGDR induced mitochondria-dependent programmed necrosis in neuronal cells. OGDR induced p53 translocation to mitochondria and association with Cyp-D, causing mitochondrial depolarization, cytochrome C release and reactive oxygen species production. Such effects were largely attenuated with pre-treatment of C19. Importantly, C19 was significantly more efficient than other known Cyp-D inhibitors in protecting neuronal cells from OGDR. These results suggest that targeting Cyp-D by C19 protects neuronal cells from OGDR.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	United States	China Pharmaceutical University	10 Jan 2025

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