PARP7 has been proven to play an important role in immunity. Substantial upregulation of PARP7 is observed in numerous cancerous cell types, consequently resulting in the inhibition of type Ⅰ interferon signaling pathways. Therefore, inhibiting the activity of PARP7 can enhance type Ⅰ interferon signaling to exert an anti-tumor immune response. In this study, we reported the identification of a newly found PARP7 inhibitor (XLY-1) with higher inhibitory activity (IC₅₀ = 0.6 nM) than that of RBN-2397 (IC₅₀ = 6.0 nM). Additionally, XYL-1 displayed weak inhibitory activity on PARP1 (IC₅₀ > 1.0 μM). Mechanism studies showed that XYL-1 could enhance the type Ⅰ interferon signaling in vitro. Pharmacodynamic experiments showed that 50 mg/kg XYL-1 could significantly inhibit tumor growth (TGI: 76.5 %) and related experiments showed that XYL-1 could restore type Ⅰ interferon signaling and promote T cell infiltration in tumor tissues. Taken together, XYL-1 shows promise as a potential candidate for developing cancer immunotherapy agents.

03 May 2024·British Journal of Cancer

Cyclin-dependent kinase 7 (CDK7) inhibitors as a novel therapeutic strategy for different molecular types of breast cancer

Review

Author: Xu, Rui ; Song, Xue ; Sun, Yang ; Qiu, Chang ; Lin, Xiaojie ; Dai, Yan ; Fang, Chen

BACKGROUNDCyclin-dependent kinase (CDK) 7 is aberrantly overexpressed in many types of cancer and is an attractive target for cancer therapy due to its dual role in transcription and cell cycle progression. Moreover, CDK7 can directly modulate the activities of estrogen receptor (ER), which is a major driver in breast cancer. Breast cancer cells have exhibited high sensitivity to CDK7 inhibition in pre-clinical studies.METHODSIn this review, we provide a comprehensive summary of the latest insights into CDK7 biology and recent advancements in CDK7 inhibitor development for breast cancer treatment. We also discuss the current application of CDK7 inhibitors in different molecular types of breast cancer to provide potential strategies for the treatment of breast cancer.RESULTSSignificant progress has been made in the development of selective CDK7 inhibitors, which show efficacy in both triple-negative breast cancer (TNBC) and hormone receptor-positive breast cancer (HR+). Moreover, combined with other agents, CDK7 inhibitors may provide synergistic effects for endocrine therapy and chemotherapy. Thus, high-quality studies for developing potent CDK7 inhibitors and investigating their applications in breast cancer therapy are rapidly emerging.CONCLUSIONCDK7 inhibitors have emerged as a promising therapeutic strategy and have demonstrated significant anti-cancer activity in different subtypes of breast cancer, especially those that have been resistant to current therapies.

01 Apr 2024·Cancer Science

SIRT7 promotes Hippo/YAP activation and cancer cell proliferation in hepatocellular carcinoma via suppressing MST1

Article

Author: Gu, Yiying ; Ding, Cong ; Yu, Tingzi ; Liu, Bohao ; Liang, Gaoshuang ; Peng, Jinying ; Zhang, Xiangwen ; Li, Zhuan ; Wang, Zhiqiang ; Tang, Xiaohui ; Tang, Wenbin

AbstractAbnormal activation of the oncogene YAP in the Hippo pathway is a major feature in liver cancer and inactivation of MST1/2 has been shown to be responsible for the overactivation of YAP that led to tumorigenesis. However, mechanisms underlying MST1/2 dysregulation remain poorly understood. RNA‐seq analysis and genome (KEGG) pathway enrichment analysis were used to identify genes and pathways that were regulated by SIRT7. qRT‐PCR, ChIP, and luciferase assay were used to investigate transcriptional regulation. Mass spectrometry, co‐immunoprecipitation and immunoprecipitation were used to exam protein–protein interaction and post‐transcriptional modification. A xenograft mouse model was used to confirm the effect of SIRT7 and SIRT7 inhibitors on hepatocellular carcinoma (HCC) proliferation in vivo. We found that SIRT7 suppresses MST1 by both transcriptional regulation and post‐transcriptional modification, which in turn promotes YAP nuclear localization and transcriptional activation in liver cancer. Mechanistically, we revealed that SIRT7 suppresses MST1 transcription by binding to the MST1 promoter and inducing H3K18 deacetylation in its promoter region. In addition, SIRT7 directly binds to and deacetylates MST1, which primes acetylation‐dependent MST1 ubiquitination and protein degradation. In clinical samples, we confirmed a negative correlation between SIRT7 and MST1 protein levels, and high SIRT7 expression correlated with elevated YAP expression and nuclear localization. In addition, SIRT7 specific inhibitor 2800Z sufficiently inhibited HCC growth by disrupting the SIRT7/MST1/YAP axis. Our data thus revealed the previously undescribed function of SIRT7 in regulating the Hippo pathway in HCC and further proved that targeting SIRT7 might provide novel therapeutic options for the treatment of liver cancer.

100 Deals associated with PARP7 inhibitors(Azkarra)

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	Azkarra Therapeutics, Inc.	24 Oct 2023

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