Antimicrobial resistance (AMR) has led to a marked reduction in the effectiveness of many antibiotics, representing a substantial and escalating concern for global health. Particularly alarming is resistance in Gram-negative bacteria due to the scarcity of therapeutic options for treating infections caused by these pathogens. This challenge is further compounded by the rising incidence of resistance to colistin, an antibiotic traditionally considered a last resort for the treatment of multi-drug resistant (MDR) Gram-negative bacterial infections. In this study, we demonstrate that adjuvants restore colistin sensitivity in vivo . We previously reported that the salicylanilide kinase inhibitor IMD-0354, which was originally developed to inhibit the human kinase IKKβ in the NFκB pathway, is a potent colistin adjuvant. Subsequent analog synthesis using an amide isostere approach led to the creation of a series of novel benzimidazole compounds with enhanced colistin adjuvant activity. Herein, we demonstrate that both IMD-0354 and a lead benzimidazole effectively restore colistin susceptibility in mouse models of highly colistin-resistant Klebsiella pneumoniae and Acinetobacter baumannii -induced peritonitis. These novel adjuvants show low toxicity in vivo , significantly reduce bacterial load, and prevent dissemination that could otherwise result in systemic infection.

2024-04-01·Molecular and cellular endocrinology

Computational drug repurposing for primary hyperparathyroidism

Article

作者: Aysan, Erhan ; Kubat Öktem, Elif ; Yazar, Metin ; Karabıyık Acar, Özge

In hyperparathyroidism (hyperPTH), excessive amounts of PTH are secreted, interfering with calcium regulation in the body. Several drugs can control the disease's side effects, but none of them is an alternative treatment to surgery. Therefore, new drug candidates are necessary. In this study, three computationally repositioned drugs, DG 041, IMD 0354, and cucurbitacin I, are evaluated in an in vitro model of hyperPTH. First, we integrated publicly available transcriptomics datasets to propose drug candidates. Using 3D spheroids derived from a single primary hyperPTH patient, we assessed their in vitro efficacy. None of the proposed drugs affected the viability of healthy cell control (HEK293) or overactive parathyroid cells at the level of toxicity. This behavior was attributed to the non-cancerous nature of the parathyroid cells, establishing the hyperPTH disease model. Cucurbitacin I and IMD 0354 exhibited a slight inverse relationship between increased drug concentrations and cell viability, whereas DG 041 increased viability. Based on these results, further studies are needed on the mechanism of action of the repurposed drugs, including determining the effects of these drugs on cellular PTH synthesis and secretion and on the metabolic pathways that regulate PTH secretion.

2024-01-01·Environmental toxicology and pharmacology

Promotion of myofibroblast differentiation through repeated treatment of fibroblasts to low concentrations of PM2.5

Article

作者: Deng, Furong ; Dvonch, J Timothy ; Huang, Steven K ; Berens, Jack P ; Craig, Nathan A ; Scruggs, Anne M ; Chen, Yahong

Exposure to particulate matter ≤ 2.5 µm (PM_2.5) is a risk factor for many lung diseases. Although the toxicologic effects of PM_2.5 on airway epithelium are well-described, the effects of PM_2.5 on fibroblasts in the lung are less studied. Here, we sought to examine the effects of PM_2.5 on the differentiation of fibroblasts into myofibroblasts. Although a single treatment of fibroblasts did not result in a change in collagen or the myofibroblast marker α-SMA, exposing fibroblasts to sequential treatments with PM_2.5 at low concentrations caused a robust increase in these proteins. Treatment of fibroblasts with IMD0354, an inhibitor to nuclear factor κB, but not with an antagonist to aryl hydrocarbon receptor, abolished the ability of PM_2.5 to induce myofibroblast differentiation. These data demonstrate that potential impact of PM_2.5 to fibroblast activation and fibrosis and support the importance of utilizing low concentrations and varying exposure protocols to toxicologic studies.

项与 IMD-0354 相关的新闻（医药）

2022-10-07

·World Pharma News

Repurposing existing drugs to fight new COVID-19 variants

Michigan State University (MSU) researchers are using big data and AI to identify current drugs that could be applied to treat new COVID-19 variants. Finding new ways to treat the novel coronavirus and its ever-changing variants has been a challenge for researchers, especially when the traditional drug development and discovery process can take years. A Michigan State University researcher and his team are taking a hi-tech approach to determine whether drugs already on the market can pull double duty in treating new COVID variants. "The COVID-19 virus is a challenge because it continues to evolve," said Bin Chen, an associate professor in the College of Human Medicine. "By using artificial intelligence and really large data sets, we can repurpose old drugs for new uses." Chen built an international team of researchers with expertise on topics ranging from biology to computer science to tackle this challenge. First, Chen and his team turned to publicly available databases to mine for the unique coronavirus gene expression signatures from 1,700 host transcriptomic profiles that came from patient tissues, cell cultures and mouse models. These signatures revealed the biology shared by COVID-19 and its variants. With the viruss signature and knowing which genes need to be suppressed and which genes need to be activated, the team was able to use a computer program to screen a drug library consisting of FDA-approved or investigational drugs to find candidates that could correct the expression of signature genes and further inhibit the coronavirus from replicating. Chen and his team discovered one novel candidate, IMD-0354, a drug that passed phase I clinical trials for the treatment of atopic dermatitis. A group in Korea later observed that it was 90-fold more effective against six COVID-19 variants than remdesivir, the first drug approved to treat COVID-19. The team further found that IMD-0354 inhibited the virus from copying itself by boosting the immune response pathways in the host cells. Based on the information learned, the researchers studied a prodrug of IMD-0354 called IMD-1041. A prodrug is an inactive substance that is metabolized within the body to create an active drug. "IMD-1041 is even more promising as it is orally available and has been investigated for chronic obstructive pulmonary disease, a group of lung diseases that block airflow and make it difficult to breathe," Chen said. "Because the structure of IMD-1041 is undisclosed, we are developing a new artificial intelligence platform to design novel compounds that hopefully could be tested and evaluated in more advanced animal models." Xing J, Shankar R, Ko M, Zhang K, Zhang S, Drelich A, Paithankar S, Chekalin E, Chua MS, Rajasekaran S, Kent Tseng CT, Zheng M, Kim S, Chen B. Deciphering COVID-19 host transcriptomic complexity and variations for therapeutic discovery against new variants. iScience. 2022 Oct 21;25(10):105068. doi: 10.1016/j.isci.2022.105068

100 项与 IMD-0354 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
特应性皮炎	临床1期	日本	IMMD, Inc.	2022-01-30
卵巢癌	临床前	日本	IMMD, Inc.	2013-04-15
心肌缺血	临床前	日本	Tokyo Medical & Dental University	2004-07-01
再灌注损伤	临床前	日本	Tokyo Medical & Dental University	2004-07-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ARVO2012	N/A	葡萄膜炎	-	IMD-0354 30 mg/kg	鹽蓋艱願憲窪艱構壓選(鬱壓窪衊艱繭網淵窪顧) = 構廠夢簾選艱蓋積獵選獵淵願淵製鑰鬱夢顧夢 (鬱築衊襯顧範憲襯衊艱 )	-	2012-03-01
				IMD-0354 10 mg/kg	鹽蓋艱願憲窪艱構壓選(鬱壓窪衊艱繭網淵窪顧) = 鹹簾襯遞憲鏇糧憲鏇築獵淵願淵製鑰鬱夢顧夢 (鬱築衊襯顧範憲襯衊艱 )