Triple negative breast cancer (TNBC) is a subtype of breast cancer with significant malignancy and poor prognosis but effective treatments are limited. Given the critical role of CDK4/6 in cell cycle and the apparent success of CDK4/6 inhibitors against certain cancer, this study attempted to utilize hydrophobic tagging technology to develop a CDK4/6 degrader against TNBC. We based on the chemical structure of the major metabolite of a clinically approved CDK4/6 inhibitor, abemaciclib, to synthesize three compounds and evaluated their in vitro cytotoxicity. LPM3770277 stood out as the most promising compound which was further confirmed by a series of binding and CDK4/6 degradation studies. LPM3770277 was able to bind to CDK4/6, and time-dependently and dose-dependently increased CDK4/6 protein degradation. Mechanistic study revealed that LPM3770277 exerted its CDK4/6 degradation effect via two machineries: proteasome and lysosome-promoted autophagy. Using in vivo TNBC xenograft cancer model, we found that LPM3770277 demonstrated superior anti-tumor efficacy and safety as compared to abemaciclib, although both compounds exerted similar effects on cell cycle arrest. In conclusion, this study for the first time developed and characterized a CDK4/6 degrader against TNBC using hydrophobic tags, which strongly suggests the viability of hydrophobic tags as a strategy to develop potential treatments against TNBC.
Lysine‐specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival. ZY0511, a highly selective and potent inhibitor of LSD1, suppressed human HCC cell proliferation in vitro and tumor growth in cell‐derived and patient‐derived HCC xenograft models in vivo. Mechanistically, ZY0511 induced mRNA expression of growth arrest and DNA damage‐inducible gene 45beta (GADD45B) by inducing histone H3 at lysine 4 (H3K4) methylation at the promoter of GADD45B, a novel target gene of LSD1. In human HCC tissues, LSD1 level was correlated with a decreased level of GADD45B, which was associated with HCC progression and predicted poor patient survival. Moreover, co‐administration of ZY0511 and DTP3, which specifically enhanced the pro‐apoptotic effect of GADD45B, effectively inhibited HCC cell proliferation both in vitro and in vivo. Collectively, our study revealed the potential value of LSD1 as a promising target of HCC therapy. ZY0511 is a promising candidate for HCC therapy through upregulating GADD45B, thereby providing a novel combinatorial strategy for treating HCC.
Activation of DNA damage repair pathways in tumor cells may reduce the treatment efficacy of platinum-based chemotherapeutic agents. Ubiquitin-specific protease 7 (USP7) is one of the deubiquitinating enzymes that can remove the ubiquitin from target proteins and protect substrate proteins from degradation. Although ubiquitin-specific protease 7(USP7) is highly expressed in cervical cancer tissues and plays an important role in DNA damage repair, the role of USP7 inhibition in the antitumor efficacy of cisplatin remains unknown. This study explored the effects and mechanisms of a USP7 inhibitor P22077 on the anti-cervical cancer efficacy of cisplatin. In in vitro studies, P22077 and cisplatin both significantly reduced HeLa cell proliferation and colony formation, and the combination produced preferable effects. In in vivo xenograft tumor model, P22077 and cisplatin both demonstrated significant antitumor efficacy. The drug combination produced greater antitumor activity than the individual drug alone. Cisplatin evoked DNA damage repair-related molecules and P22077 tended to prevent this change. The drug combination produced higher cell death rate than the individual drug alone. Collectively, These results suggest that the USP7 inhibitor P22077 alone has significant antitumor efficacy and also can enhance the antitumor effects of cisplatin. The USP7 inhibitor P22077 combined with cisplatin may be an effective treatment strategy for cervical cancer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.