AbstractBackgroundAdenosine deaminases acting on RNA 1 (ADAR1), an RNA editing enzyme, holds a role in cancer, inflammation, and immunity. However, its specific function in the nephropathy and high-glucose-induced human renal tubular epithelial cells (HK-2) injury in diabetic db/db mice is not clear.MethodsThis study explored the expression characteristics of ADAR1 in proximal renal tubular cells of diabetic db/db mice, examining its function in the mechanism of high-glucose-induced HK-2 cell injury. Furthermore, it elucidated the molecular mechanism underlying the protective effect of ADAR1, the regulation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt)/mammalian target of the rapamycin (mTOR) signaling. We observed a decrease in ADAR1 expression in proximal tubular cells of diabetic db/db mice, accompanied by an increase in the expression of inflammation-related markers (PI3K/AKT/mTOR).ResultsWe constructed and validated ADAR1-overexpression plasmids and used an ADAR1 inhibitor (8-azaadenosine) to carry out cell experiments. The upregulation of ADAR1 expression alleviated high-glucose-induced endoplasmic reticulum stress, reduced HK-2 cell apoptosis, and reduced the expression of inflammation-related indicators (PI3K/AKT/mTOR).ConclusionTaken together, the pivotal roles of ADAR1 in the progression of proximal renal tubulopathy and the mechanism of high-glucose-induced HK-2 injury in diabetic db/db mice suggest that ADAR1 may be a potential key factor in slowing the progression of diabetic kidney disease.

01 Sep 2024·Genomics

Dissecting transposable elements and endogenous retroviruses upregulation by HDAC inhibitors in leiomyosarcoma cells: Implications for the interferon response

Article

Author: Gualandi, Nicolò ; Bertozzo, Alessio ; Minisini, Martina ; Brancolini, Claudio

Transposable elements (TEs) are of interest as immunomodulators for cancer therapies. TEs can fold into dsRNAs that trigger the interferon response. Here, we investigated the effect of different HDAC inhibitors (HDACIs) on the expression of TEs in leiomyosarcoma cells. Our data show that endogenous retroviruses (ERVs), especially ERV1 elements, are upregulated after treatment with HDAC1/2/3-specific inhibitors. Surprisingly, the interferon response was not activated. We observed an increase in A-to-I editing of upregulated ERV1. This could have an impact on the stability of dsRNAs and the activation of the interferon response. We also found that H3K27ac levels are increased in the LTR12 subfamilies, which could be regulatory elements controlling the expression of proapoptotic genes such as TNFRSF10B. In summary, we provide a detailed characterization of TEs modulation in response to HDACIs and suggest the use of HDACIs in combination with ADAR inhibitors to induce cell death and support immunotherapy in cancer.

01 May 2024·Biomedicine & Pharmacotherapy

Synergistic targeting of TrxR1 and ATM/AKT pathway in human colon cancer cells

Article

Author: Chen, Yinghua ; Xia, Yiqun ; Xu, Chenxin ; Ni, Daoyong ; Zhang, Yafei ; Lu, Hui ; Wang, Junqi ; Qiu, Chenyu ; Shen, Xin ; Zou, Peng ; Zheng, Peisen ; Cui, Ri ; Xiao, Zhongxiang

Thioredoxin reductase 1 (TrxR1) has emerged as a promising target for cancer therapy. In our previous research, we discovered several new TrxR1 inhibitors and found that they all have excellent anti-tumor activity. At the same time, we found these TrxR1 inhibitors all lead to an increase in AKT phosphorylation in cancer cells, but the detailed role of AKT phosphorylation in TrxR1 inhibitor-mediated cell death remains unclear. In this study, we identified the combination of AKT and TrxR1 inhibitor displayed a strong synergistic effect in colon cancer cells. Furthermore, we demonstrated that the synergistic effect of auranofin (TrxR1 inhibitor) and MK-2206 (AKT inhibitor) was caused by ROS accumulation. Importantly, we found that ATM inhibitor KU-55933 can block the increase of AKT phosphorylation caused by auranofin, and exhibited a synergistic effect with auranofin. Taken together, our study demonstrated that the activation of ATM/AKT pathway is a compensatory mechanism to cope with ROS accumulation induced by TrxR1 inhibitor, and synergistic targeting of TrxR1 and ATM/AKT pathway is a promising strategy for treating colon cancer.

News (Medical) associated with ADAR1 inhibitors (Accent Therapeutics)

09 Oct 2024

·www.prnewswire.com

BridGene Biosciences to Present Three Novel Covalent Inhibitors at the 36th EORTC-NCI-AACR Symposium

Presentations on cMyc, ADAR1, and PAX8 inhibitors to be held on October 25, 2024 SAN JOSE, Calif., Oct. 9, 2024 /PRNewswire/ -- BridGene Biosciences, a leader in the discovery of small molecule drugs for traditionally "hard-to-drug" targets, today announced it will present three groundbreaking posters at the American Association for Cancer Research (AACR) 2024 Annual Meeting in Barcelona, on October 25, 2024. The posters will showcase the company's latest advancements in the development of covalent inhibitors for key oncogenic targets, including cMyc, ADAR1, and PAX8, each representing promising new treatment avenues for various cancers. "These three presentations represent significant strides in our mission to develop novel therapeutics for cancer patients," said Ping Cao, Ph.D., Co-Founder and CEO of BridGene Biosciences. "By focusing on these high-value, historically hard-to-drug targets, we aim to create first-in-class therapies that address critical gaps in cancer treatment. Our platform continues to unlock new possibilities in drug discovery, and we are excited to share these advancements with the scientific community at AACR." BridGene's work on cMyc, titled "Discovery of a Covalent Inhibitor Targeting the Undruggable Oncogene cMyc," focuses on overcoming the challenges posed by its intrinsically disordered structure, which has historically rendered the protein hard-to-drug. Through its proprietary Isobaric Mass Tagged Affinity Characterization (IMTAC™) platform, BridGene identified two hit compounds, which effectively inhibit cMyc signaling. These inhibitors showed potent activity in reducing transcriptional function and offering a potential therapeutic strategy for cancers driven by cMyc amplification, which accounts for nearly one-third of all tumors. In addition to its work on cMyc, BridGene will present research titled "Discovery of a Novel Covalent ADAR1 Inhibitor," focusing on a novel covalent inhibitor targeting ADAR1, an enzyme that plays a critical role in RNA editing and immune suppression in cancer. By inhibiting ADAR1, BridGene's compounds, could be expected to enhance the efficacy of immune checkpoint blockade therapies. This research highlights the potential for ADAR1 inhibitors to reshape the tumor microenvironment, paving the way for more effective immunotherapies. BridGene's third poster presentation, "Discovery of a Novel Covalent PAX8 Inhibitor," will unveil a covalent inhibitor of PAX8, a transcription factor linked to poor prognosis in renal cell carcinoma and ovarian cancer. Utilizing its IMTAC™ platform, BridGene discovered a compound that disrupts the DNA binding activity of PAX8. This discovery opens the door to new therapeutic strategies for cancers with elevated PAX8 expression, which have traditionally been difficult to target. About BridGene Biosciences BridGene is a biotechnology company focused on discovering and developing innovative small molecules that drug traditionally undruggable targets, providing new paths to treat diseases. By using its proprietary chemoproteomic platform, IMTAC™, BridGene can screen small molecules against all proteins in live cells to discover drug candidates for high-value and previously undruggable targets. BridGene is advancing a diversified pipeline of first-in-class drugs for targets in multiple disease areas. For more information, visit . Contact Tiberend Strategic Advisors, Inc. Jonathan Nugent (investors) 205-566-3026 [email protected] Dave Schemelia (media) 609-468-9325 [email protected] SOURCE BridGene Biosciences WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

AACRImmunotherapy

10 Jun 2016

·medcitynews.com

Small-molecule tool could reduce leukemia cell regeneration

Chronic myeloid leukemia blood cells Researchers led by a team at the University of California, San Diego, School of Medicine have determined that overexpression of the ADAR1 enzyme, which is responsible for RNA editing, ramps up cellular regeneration, causing white blood cell precursors to develop into leukemia stem cells. Even more significantly, the investigators determined that a small-molecule tool could counteract the overexpression of ADAR1 and reduce the regeneration of leukemia cells. The study was published Thursday on the website of the journal Cell Stem Cell. “We showed that cancer stem cells co-opt an RNA editing system to clone themselves. What’s more, we found a method to dial it down,” principal investigator Dr. Catriona Jamieson said in a news release. Jamieson is chief of regenerative medicine at UCSD. To conduct the experiment, the team of 20 researchers transplanted human blast crisis chronic myeloid leukemia cells into mice. Using this mouse model, they found that white blood cells with a genetic mutation associated with leukemia were more sensitive to inflammatory signals. The inflammation in turn unleashed the ADAR1 enzyme governing RNA editing. The RNA editing by the ADAR1 enzyme subsequently slowed microRNA molecules known as let-7, which have been shown to inhibit the growth of tumor cells. The research team then determined that dampening the expression of ADAR1 using a small-molecule tool called 8-Aza significantly reduced the regeneration of the blast crisis chronic myeloid leukemia cells by 40 percent when compared with control cells. Jamieson said that assessing ADAR1 expression will be a useful tool for predicting cancer progression. “In addition, inhibiting this enzyme represents a unique therapeutic vulnerability in cancer stem cells with active inflammatory signaling that may respond to pharmacologic inhibitors of inflammation sensitivity or selective ADAR1 inhibitors that are currently being developed,” she said. Dr. Karim Mekhail, an associate professor of laboratory medicine and pathobiology at the University of Toronto, who researches RNA and human disease, commented that the study provides insights regarding the interplay between RNA and cancer development. “Our genetic information flows from DNA to RNA to protein,” Mekhail said. “While we commonly associate human diseases including cancer to mutations in DNA, we now also appreciate that cancer is driven in large part by RNA molecules and the processes controlling them. This study is very important as it identifies how the RNA editing function of ADAR1 contributes to a particularly aggressive form of cancer while opening the door to new prognostic and therapeutic avenues.”

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Indication	Highest Phase	Country/Location	Organization	Date
Non-Small Cell Lung Cancer	Preclinical	US	Accent Therapeutics, Inc.Startup	22 Nov 2023
Ovarian Cancer	Preclinical	US	Accent Therapeutics, Inc.Startup	22 Nov 2023
Squamous Cell Carcinoma of Head and Neck	Preclinical	US	Accent Therapeutics, Inc.Startup	22 Nov 2023
Triple Negative Breast Cancer	Preclinical	US	Accent Therapeutics, Inc.Startup	22 Nov 2023

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