AbstractOvarian endometrioma (OE) is a common gynecological condition characterized by the formation of “chocolate cysts”. Recent research indicates that the cyst fluid acts as a “toxic environment” for the ovary and plays a significant role in the development of OE, with macrophages being pivotal. However, the specific molecular and cellular mechanisms of it are not fully understood. In this study, clinical samples are integrated, single‐cell sequencing, in vivo and in vitro experimental models to comprehensively investigate the effects of OE fluid on ovarian function and the mechanisms of it. Combined with bioinformatics analysis and experimental validation, the findings demonstrate that OE fluid can cause ovarian function decline, which associated with inflammatory response, and mitochondrial dysfunction and cellular senescence, while activating the cGAS/STING signaling pathway. As a STING inhibitor, H‐151 effectively alleviates ovarian dysfunction, inflammatory state and cell apoptosis induced by OE fluid. Furthermore, it is also discovered that H‐151 can inhibit OE fluid‐induced mitochondrial dysfunction and cellular senescence. These findings provide important theoretical and experimental foundations for further research and development of STING inhibitors as potential drugs for treating ovarian dysfunction.

2024-08-01·Redox Biology

Development of nitroalkene-based inhibitors to target STING-dependent inflammation

Article

作者: Salvatore, Sonia R ; Thielke, Anne L ; Colussi, Nicole ; Pitts, Mareena ; Alvarez, Beatriz ; Schopfer, Francisco J ; Hansen, Anne Louise ; Gunderstofte, Camilla ; Turell, Lucia ; Holm, Christian K ; Villacorta, Luis ; Chang, Fei ; Goldbach-Mansky, Raphaela

Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for in vitro and in vivo STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a β-nitrostyrene moiety, potently inhibited STING activity in vitro and relieved STING-dependent inflammation in vivo. This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development.

2024-06-01·Shock

INHIBITORS OF INORGANIC POLYPHOSPHATE AND NUCLEIC ACIDS ATTENUATE IN VITRO THROMBIN GENERATION IN PLASMA FROM TRAUMA PATIENTS

Article

作者: Smith, Stephanie A. ; Spears, Grant M. ; Zietlow, John ; Park, Myung S. ; Yudin, Nikoli ; Kozar, Rosemary A. ; Bailey, Kent R. ; Kizhakkedathu, Jayachandran N. ; La, Chanel C. ; Navarro, Sergio M. ; Goswami, Julie ; Dong, Jing-Fei ; Morrissey, James H. ; Vappala, Sreeparna ; MacArthur, Taleen A.

ABSTRACTBackground:Inorganic polyphosphate (polyP) is a procoagulant polyanion. We assessed the impact of polyP inhibition on thrombin generation after trauma using the novel polyP antagonists, macromolecular polyanion inhibitor 8 (MPI 8), and universal heparin reversal agent 8 (UHRA-8).Methods:Plasma thrombin generation (calibrated automated thrombogram, CAT), in 56 trauma patients and 39 controls +/− MPI 8 and UHRA-8 (50 μg/mL), was expressed as lag time (LT, minutes), peak height (PH, nM), and time to peak (ttPeak, minutes), with change in LT (ΔLT) and change in ttPeak (ΔttPeak) quantified. Results expressed in median and quartiles [Q1, Q3], Wilcoxon matched-pairs testing,P< 0.05 significant.Results:Trauma patients had greater baseline PH than controls (182.9 [121.0, 255.2]; 120.5 [62.1, 174.8],P< 0.001). MPI 8 treatment prolonged LT and ttPeak in trauma (7.20 [5.88, 8.75]; 6.46 [5.45, 8.93],P= 0.020; 11.28 [8.96, 13.14]; 11.00 [8.95, 12.94],P= 0.029) and controls (7.67 [6.67, 10.50]; 6.33 [5.33, 8.00],P< 0.001; 13.33 [11.67, 15.33]; 11.67 [10.33, 13.33],P< 0.001). UHRA-8 treatment prolonged LT and ttPeak and decreased PH in trauma (9.09 [7.45, 11.33]; 6.46 [5.45, 8.93]; 14.02 [11.78, 17.08]; 11.00 [8.95, 12.94]; 117.4 [74.5, 178.6]; 182.9 [121.0, 255.2]) and controls (9.83 [8.00, 12.33]; 6.33 [5.33, 8.00]; 16.67 [14.33, 20.00]; 11.67 [10.33, 13.33]; 55.3 [30.2, 95.9]; 120.5 [62.1, 174.8]), allP< 0.001. Inhibitor effects were greater for controls (greater ΔLT and ΔttPeak for both inhibitors,P< 0.001).Conclusion:PolyP inhibition attenuates thrombin generation, though to a lesser degree in trauma than in controls, suggesting that polyP contributes to accelerated thrombin generation after trauma.

项与 STING antagonists(Merck) 相关的新闻（医药）

2024-03-14

·Pharmaceutical Technology

Novartis exercises option to acquire IFM Due for $835m

The collaboration between IFM Due and Novartis began in September 2019. Credit: lucarista / Shutterstock.com. Novartis has exercised an option for the acquisition of all outstanding capital stock of IFM Therapeutics subsidiary IFM Due for $835m. The strategic acquisition will grant Novartis the complete rights to IFM Due’s portfolio of STING antagonists, which address a range of serious inflammation-driven diseases. IFM Due, established in February 2019, develops small molecule orally available drug candidates targeting the cyclic GMP-AMP synthase, a stimulator of the interferon genes (cGAS-STING) pathway, which is implicated in several serious diseases. The collaboration between IFM Due and Novartis began in September 2019 when the companies made an option and partnership agreement. Novartis agreed to fund research and development by IFM Due for the cGAS-STING programme in exchange for an option to acquire the company. See Also: Novartis files patent for combination therapy for b-cell lymphoma with CD19 car and BCL2 inhibitor Johnson & Johnson acquires Ambrx Biopharma for $2bn With the option exercised, IFM received an upfront payment of $90m from Novartis and is also entitled to milestone payments of $745m. The acquisition is a significant move for Novartis, as it will secure complete rights for IFM Due’s portfolio comprising STING antagonists. These assets have the potential to treat serious inflammation-driven ailments characterised by excessive interferon and other pro-inflammatory cytokine signalling. The cGAS-STING pathway functions within the innate immune system to sense cytosolic DNA, a signal of cellular danger, and then triggers a STING-dependent inflammatory response. Inappropriate activation of this pathway can result from genetic mutations or factors such as mitochondrial dysfunction, leading to diseases characterised by excessive inflammation. Novartis immunology research global head Richard Siegel said: “The acquisition of IFM Due represents the culmination of a highly productive, four-year preclinical collaboration between Novartis and IFM to develop novel small-molecule STING inhibitors with the potential to treat a spectrum of inflammatory diseases. “We are excited to advance IFM Due’s STING programme and leverage our deep expertise in inflammation science to bring forward transformative medicines that address major unmet patient needs.”

并购免疫疗法

2024-03-13

·FierceBiotech

Novartis hits the cGAS, taking option to buy IFM unit for $90M upfront

Novartis has gained full rights to a portfolio of STING antagonists. Novartis is stepping on the cGAS. Three years after securing an option on an IFM Therapeutics subsidiary, the Swiss drugmaker has accelerated into the deal and paid $90 million upfront for small molecules that inhibit the cGAS-STING pathway. Researchers have uncovered the role the cGAS-STING pathway plays in the mediation of inflammation in response to infection, cellular stress and tissue damage over the past decade or so, spurring interest in targeting the axis to treat autoimmune and degenerative diseases. Novartis threw its weight behind the push by agreeing to fund research at an IFM subsidiary, IFM Due, in 2019. Having bankrolled the preclinical research, Novartis has seen enough promise to warrant pumping more money into the program. The drugmaker has paid $90 million upfront and committed up to $745 million in milestone payments to acquire IFM Due. In return, Novartis has gained full rights to a portfolio of STING antagonists with potential applications in the treatment of a range of diseases characterized by excessive interferon and other pro-inflammatory cytokine signaling. This morning's release lacks details of the status of the molecules, but the original plan was for Novartis to fund IFM Due through late-stage preclinical development of the lead program. Drug developers are attacking the cGAS-STING pathway from multiple angles. One approach is to inhibit cGAS, an enzyme that activates STING. Ventus Therapeutics recently began a phase 1 clinical trial of a cGAS inhibitor, while Nimbus Therapeutics has a discovery-stage cGAS program in its pipeline. Other groups, including Bayer and Novartis, have inked deals for antagonists of STING. Novartis’ decision to take up its option on IFM Due comes four years after it paid $310 million to buy another of the biotech’s subsidiaries. The earlier deal gave Novartis control of the clinical and preclinical NLRP3 antagonists in development at IFM Tre. IFM sold preclinical STING and NLRP3 agonist programs to Bristol Myers Squibb in 2017.

临床1期并购引进/卖出

2024-03-13

·Endpoints

Novartis returns for another piece of IFM Therapeutics

After buying a portion of IFM Therapeutics’ pipeline in 2019, Novartis is back for a second helping as it bags its STING antagonists. The Swiss Big Pharma had paid $90 million upfront a few years ago for an option and collaboration agreement and would pay up to $745 million in milestones if it opted to acquire IFM’s subsidiary IFM Due. Its time is due, and the companies said Wednesday that Novartis will have full rights to IFM Due’s portfolio of STING antagonists, which could turn into treatments for inflammation-driven diseases. The deal is a result of a four-year preclinical tie-up on small molecules.

引进/卖出并购

100 项与 STING antagonists(Merck) 相关的药物交易

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