作者: Bittencourt, Clarissa A ; Martin, Renan P ; Branquinho, Jéssica ; Arata, Júlia G ; Pesquero, João B ; Neves, Raquel L ; Araújo, Ronaldo C ; Icimoto, Marcelo Y

OBJECTIVE AND DESIGNKinin B1 receptor (B1R) has a key role in adipocytes to protect against obesity and glycemic metabolism, thus becoming a potential target for regulation of energy metabolism and adipose tissue thermogenesis.MATERIAL OR SUBJECTSKinin B1 knockout mice (B1KO) were subjected to acute induction with CL 316,243 and chronic cold exposure.METHODSMetabolic and histological analyses, gene and protein expression and RNA-seq were performed on interscapular brown adipose tissue (iBAT) and inguinal white adipose tissue (iWAT) of mice.RESULTSB1KO mice, under acute effect of CL 316,243, exhibited increased energy expenditure and upregulated thermogenic genes in iWAT. They were also protected from chronic cold, showing enhanced non-shivering thermogenesis with increased iBAT mass (~ 90%) and recruitment of beige adipocytes in iWAT (~ 50%). Positive modulation of thermogenic and electron transport chain genes, reaching a 14.5-fold increase for Ucp1 in iWAT. RNA-seq revealed activation of the insulin signaling pathways for iBAT and oxidative phosphorylation, tricarboxylic acid cycle, and browning pathways for iWAT.CONCLUSIONB1R deficiency induced metabolic and gene expression alterations in adipose tissue, activating thermogenic pathways and increasing energy metabolism. B1R antagonists emerge as promising therapeutic targets for regulating obesity and associated metabolic disorders, such as inflammation and diabetes.

2023-12-31·Bioengineered

A data-driven machine learning approach for discovering potent LasR inhibitors

Article

作者: Wezen, Xavier Chee ; Theng, Lau Bee ; Palombo, Enzo A ; Koh, Christabel Ming Ming ; San, Hwang Siaw ; Xuan, Christopher Ha Heng ; Ping, Lilian Siaw Yung

The rampant spread of multidrug-resistant Pseudomonas aeruginosa strains severely threatens global health. This severity is compounded against the backdrop of a stagnating antibiotics development pipeline. Moreover, with many promising therapeutics falling short of expectations in clinical trials, targeting the las quorum sensing (QS) system remains an attractive therapeutic strategy to combat P. aeruginosa infection. Thus, our primary goal was to develop a drug prediction algorithm using machine learning to identify potent LasR inhibitors. In this work, we demonstrated using a Multilayer Perceptron (MLP) algorithm boosted with AdaBoostM1 to discriminate between active and inactive LasR inhibitors. The optimal model performance was evaluated using 5-fold cross-validation and test sets. Our best model achieved a 90.7% accuracy in distinguishing active from inactive LasR inhibitors, an area under the Receiver Operating Characteristic Curve value of 0.95, and a Matthews correlation coefficient value of 0.81 when evaluated using test sets. Subsequently, we deployed the model against the Enamine database. The top-ranked compounds were further evaluated for their target engagement activity using molecular docking studies, Molecular Dynamics simulations, MM-GBSA analysis, and Free Energy Landscape analysis. Our data indicate that several of our chosen top hits showed better ligand-binding affinities than naringenin, a competitive LasR inhibitor. Among the six top hits, five of these compounds were predicted to be LasR inhibitors that could be used to treat P. aeruginosa-associated infections. To our knowledge, this study provides the first assessment of using an MLP-based QSAR model for discovering potent LasR inhibitors to attenuate P. aeruginosa infections.

2023-12-01·Biochemical Pharmacology

Discovery of novel organoarsenicals as robust thioredoxin reductase inhibitors for oxidative stress mediated cancer therapy

Article

作者: Liu, Tingting ; She, Wenyan ; Liu, Yujiao ; Liu, Yi ; Shi, Xuemin

Targeting overexpressed thioredoxin reductase (TrxR) in cancer cells to induce oxidative stress has been proved to be an effective strategy for cancer therapy. However, the treatment was hindered by the low efficiency and frequent administration of TrxR inhibitors, and hence more potent TrxR inhibitors were urgently needed. Herein, we designed and synthesized a series of TrxR inhibitors based on arsenicals. Among these, compound 1d inhibited the proliferation of a variety of cancer cells at low micromolar concentrations and exhibited low toxicity to normal cells. Importantly, compound 1d induced the accumulation of reactive oxygen species (ROS) by inhibiting the TrxR activity, further causing the collapse of the redox system, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and DNA damage, followed by oxidative stress-induced cell apoptosis. In vivo data showed that, compared with the clinical TrxR inhibitor auranofin (AUR), compound 1d could more effectively eliminate tumors by 90 % at a dose of 1.5 mg/kg without any obvious side effects. These results indicated that compound 1d was a potent TrxR inhibitor against cancer.

项与 B1R inhibitors(Alpha-9 Theranostics) 相关的新闻（医药）

2024-01-05

·GlobeNewswire-Health Care

Basilea provides portfolio status update

Clinical portfolio substantially strengthened through business development in 2023; two phase 3 studies expected to start in 2024Cresemba in-market sales of USD 445 million, increased 22% year-on-year, in 12-month period ending September 2023; 6-months market exclusivity extension granted in the USFDA PDUFA target action date on ceftobiprole US NDA April 3; US commercialization partner expected to be announced prior to FDA decision Allschwil, Switzerland, January 5, 2024 Basilea Pharmaceutica Ltd, Allschwil (SIX: BSLN), a commercial-stage biopharmaceutical company committed to meeting the needs of patients with severe bacterial and fungal infections, reported today on the progress within its R&D portfolio in 2023 and upcoming milestones and timelines. David Veitch, Chief Executive Officer, said: “We have achieved significant milestones in 2023 and remain committed to executing our strategy to drive long-term value creation. With the addition of three new assets to our clinical development pipeline, led by the very promising antifungal fosmanogepix, we are delivering on our goal of creating a balanced portfolio of innovative drug candidates for the treatment of severe bacterial and fungal infections. Furthermore, we have established ourselves as the partner of choice for companies seeking support in the development of their assets, with a focus on differentiation and commercial positioning. The continued commercial success of Cresemba and, pending US approval, the increasing revenue contributions from Zevtera, provide us with the financial strength to both advance our new programs and continue to expand our exciting R&D portfolio, supporting us in achieving our strategic goal of becoming a leading anti-infectives company.” Maintaining its strong momentum, the commercial performance of Cresemba triggered a number of milestone payments to Basilea. By year-end 2023, Cresemba was marketed in more than 70 countries, including the United States (US), most EU member states, China and Japan. According to the latest available market data, total global in-market sales of Cresemba in the twelve-month period between October 2022 and September 2023 amounted to USD 445 million, a 22 percent growth year-on-year.1 Portfolio key highlights 2023 Cresemba® (isavuconazole) commercial lifespan extension In December, the US Food and Drug Administration (FDA) approved the expanded use of Cresemba in children with invasive aspergillosis and invasive mucormycosis.2 The FDA also granted pediatric exclusivity, which extends the period of market exclusivity for Cresemba in the United States by an additional six months to September 2027.In August, Basilea submitted a similar application for a pediatric label extension of Cresemba in the European Union and anticipates a decision by the European Commission around mid-2024. If the pediatric extension is granted, Cresemba would be eligible to an additional two years of market exclusivity in the European Union, until October 2027. Zevtera® (ceftobiprole) US NDA under review In September, data from the successful phase 3 study, ERADICATE, which evaluated ceftobiprole for the treatment of bacterial bloodstream infections (bacteremia) caused by Staphylococcus aureus in adult patients, were published in the New England Journal of Medicine, supporting its potent activity in treating serious bacterial infections.3In August, Basilea submitted a New Drug Application (NDA) to the FDA, seeking approval of ceftobiprole for the treatment of patients in three indications: Staphylococcus aureus bacteremia (SAB), including right-sided infective endocarditis, acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).4 The FDA accepted the submission in October and set April 3, 2024, as the Prescription Drug User Fee Act (PDUFA) target action date, i.e. the regulatory decision date. Basilea expects to enter into a commercialization partnership agreement for ceftobiprole in the US prior to the FDA decision. Pipeline broadened with promising new clinical drug candidates In November, Basilea acquired the rights to the phase-3-ready, first-in-class, broad-spectrum antifungal fosmanogepix, one of the most attractive agents currently in clinical development, with activity against both yeasts, including Candida auris, classified as acritical priority pathogen by the World Health Organization (WHO), and molds that are resistant to other antifungal agents.Acquisition of another potential first-in-class antifungal, now named BAL2062, with activity against Aspergillus molds, including azole-resistant strains and other fungiAcquisition of evaluation license for the novel antibiotic, tonabacase, for the treatment of infections caused by Staphylococcus aureus, including multi-drug resistant strains and those forming difficult-to-eradicate biofilms. For fosmanogepix, Basilea anticipates to start a phase 3 study in invasive yeast infections mid-2024 and a phase 3 study in invasive mold infections, by year-end 2024. For BAL2062 and tonabacase, the focus for 2024 will be on preclinical profiling in order to define the optimal positioning and clinical development plans for these assets. Following a re-prioritization of its earlier stage research pipeline and re-allocation of resources, Basilea decided at year-end 2023 to discontinue the preclinical program on inhibitors of DXR, an enzyme in the bacterial isoprenoid biosynthesis pathway.5 Throughout 2024, we aim to continue expanding our R&D portfolio, through the identification of innovative, commercially attractive assets, addressing unmet medical needs in the treatment of severe fungal and bacterial diseases. About Basilea Basilea is a commercial-stage biopharmaceutical company founded in 2000 and headquartered in Switzerland. We are committed to discovering, developing and commercializing innovative drugs to meet the needs of patients with severe bacterial and fungal infections. We have successfully launched two hospital brands, Cresemba for the treatment of invasive fungal infections and Zevtera for the treatment of bacterial infections. In addition, we have preclinical and clinical anti-infective assets in our portfolio. Basilea is listed on the SIX Swiss Exchange (SIX: BSLN). Please visit basilea.com. Disclaimer This communication expressly or implicitly contains certain forward-looking statements, such as "believe", "assume", "expect", "forecast", "project", "may", "could", "might", "will" or similar expressions concerning Basilea Pharmaceutica Ltd, Allschwil and its business, including with respect to the progress, timing and completion of research, development and clinical studies for product candidates. Such statements involve certain known and unknown risks, uncertainties and other factors, which could cause the actual results, financial condition, performance or achievements of Basilea Pharmaceutica Ltd, Allschwil, to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Basilea Pharmaceutica Ltd, Allschwil is providing this communication as of this date and does not undertake to update any forward-looking statements contained herein as a result of new information, future events or otherwise. For further information, please contact: Peer Nils Schröder, PhD Head of Corporate Communications & Investor RelationsBasilea Pharmaceutica International Ltd, Allschwil Hegenheimermattweg 167b4123 AllschwilSwitzerland Phone +41 61 606 1102 E-mail media_relations@basilea.cominvestor_relations@basilea.com This press release can be downloaded from www.basilea.com. References IQVIA Analytics Link, September 2023. In-market sales reported as moving annual total (MAT) in US dollar.Cresemba US prescribing information: https://www.astellas.us/docs/cresemba.pdf [Accessed: January 4, 2024]ERADICATE (SAB): ClinicalTrials.gov identifier NCT03138733T. L. Holland, S. E. Cosgrove, S. B. Doernberg et al. Ceftobiprole for treatment of complicated Staphylococcus aureus bacteremia. New England Journal of Medicine 2023 (389), 1390-1401; DOI: 10.1056/NEJMoa2300220Basilea’s ceftobiprole phase 3 program is funded in part with federal funds from the US Department of Health and Human Services (HHS); Administration for Strategic Preparedness and Response (ASPR); Biomedical Advanced Research and Development Authority (BARDA), under contract number HHSO100201600002C. Basilea has been awarded approximately USD 112 million, or approximately 75 percent of the costs related to the phase 3 studies in SAB and acute bacterial skin and skin structure infections (ABSSSI), regulatory activities and non-clinical work.Research reported in this press release is supported by CARB-X. CARB-X’s funding for the preclinical program on DXR inhibitors is provided in part with federal funds from the US Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority; under agreement number: 75A50122C00028, and by awards from Wellcome (WT224842), Germany’s Federal Ministry of Education and Research (BMBF), the UK Global Antimicrobial Resistance Innovation Fund (GAMRIF) funded by the UK Government Department of Health and Social Care (DHSC), and the Bill & Melinda Gates Foundation. The content of this press release is solely the responsibility of the authors and does not necessarily represent the official views of CARB-X or any of its funders. Attachments Press release (PDF)

临床3期申请上市上市批准并购

2024-01-05

·BioSpace

Basilea provides portfolio status update - Jan 05, 2024

Clinical portfolio substantially strengthened through business development in 2023; two phase 3 studies expected to start in 2024 Cresemba in-market sales of USD 445 million, increased 22% year-on-year, in 12-month period ending September 2023; 6-months market exclusivity extension granted in the US FDA PDUFA target action date on ceftobiprole US NDA April 3; US commercialization partner expected to be announced prior to FDA decision Allschwil, Switzerland, January 5, 2024 Basilea Pharmaceutica Ltd, Allschwil (SIX: BSLN), a commercial-stage biopharmaceutical company committed to meeting the needs of patients with severe bacterial and fungal infections, reported today on the progress within its R&D portfolio in 2023 and upcoming milestones and timelines. David Veitch, Chief Executive Officer, said: “We have achieved significant milestones in 2023 and remain committed to executing our strategy to drive long-term value creation. With the addition of three new assets to our clinical development pipeline, led by the very promising antifungal fosmanogepix, we are delivering on our goal of creating a balanced portfolio of innovative drug candidates for the treatment of severe bacterial and fungal infections. Furthermore, we have established ourselves as the partner of choice for companies seeking support in the development of their assets, with a focus on differentiation and commercial positioning. The continued commercial success of Cresemba and, pending US approval, the increasing revenue contributions from Zevtera, provide us with the financial strength to both advance our new programs and continue to expand our exciting R&D portfolio, supporting us in achieving our strategic goal of becoming a leading anti-infectives company.” Maintaining its strong momentum, the commercial performance of Cresemba triggered a number of milestone payments to Basilea. By year-end 2023, Cresemba was marketed in more than 70 countries, including the United States (US), most EU member states, China and Japan. According to the latest available market data, total global in-market sales of Cresemba in the twelve-month period between October 2022 and September 2023 amounted to USD 445 million, a 22 percent growth year-on-year.1 Portfolio key highlights 2023 Cresemba® (isavuconazole) commercial lifespan extension In December, the US Food and Drug Administration (FDA) approved the expanded use of Cresemba in children with invasive aspergillosis and invasive mucormycosis.2 The FDA also granted pediatric exclusivity, which extends the period of market exclusivity for Cresemba in the United States by an additional six months to September 2027. In August, Basilea submitted a similar application for a pediatric label extension of Cresemba in the European Union and anticipates a decision by the European Commission around mid-2024. If the pediatric extension is granted, Cresemba would be eligible to an additional two years of market exclusivity in the European Union, until October 2027. Zevtera® (ceftobiprole) US NDA under review In September, data from the successful phase 3 study, ERADICATE, which evaluated ceftobiprole for the treatment of bacterial bloodstream infections (bacteremia) caused by Staphylococcus aureus in adult patients, were published in the New England Journal of Medicine, supporting its potent activity in treating serious bacterial infections.3 In August, Basilea submitted a New Drug Application (NDA) to the FDA, seeking approval of ceftobiprole for the treatment of patients in three indications: Staphylococcus aureus bacteremia (SAB), including right-sided infective endocarditis, acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).4 The FDA accepted the submission in October and set April 3, 2024, as the Prescription Drug User Fee Act (PDUFA) target action date, i.e. the regulatory decision date. Basilea expects to enter into a commercialization partnership agreement for ceftobiprole in the US prior to the FDA decision. Pipeline broadened with promising new clinical drug candidates In November, Basilea acquired the rights to the phase-3-ready, first-in-class, broad-spectrum antifungal fosmanogepix, one of the most attractive agents currently in clinical development, with activity against both yeasts, including Candida auris, classified as acritical priority pathogen by the World Health Organization (WHO), and molds that are resistant to other antifungal agents. Acquisition of another potential first-in-class antifungal, now named BAL2062, with activity against Aspergillus molds, including azole-resistant strains and other fungi Acquisition of evaluation license for the novel antibiotic, tonabacase, for the treatment of infections caused by Staphylococcus aureus, including multi-drug resistant strains and those forming difficult-to-eradicate biofilms. For fosmanogepix, Basilea anticipates to start a phase 3 study in invasive yeast infections mid-2024 and a phase 3 study in invasive mold infections, by year-end 2024. For BAL2062 and tonabacase, the focus for 2024 will be on preclinical profiling in order to define the optimal positioning and clinical development plans for these assets. Following a re-prioritization of its earlier stage research pipeline and re-allocation of resources, Basilea decided at year-end 2023 to discontinue the preclinical program on inhibitors of DXR, an enzyme in the bacterial isoprenoid biosynthesis pathway.5 Throughout 2024, we aim to continue expanding our R&D portfolio, through the identification of innovative, commercially attractive assets, addressing unmet medical needs in the treatment of severe fungal and bacterial diseases. About Basilea Basilea is a commercial-stage biopharmaceutical company founded in 2000 and headquartered in Switzerland. We are committed to discovering, developing and commercializing innovative drugs to meet the needs of patients with severe bacterial and fungal infections. We have successfully launched two hospital brands, Cresemba for the treatment of invasive fungal infections and Zevtera for the treatment of bacterial infections. In addition, we have preclinical and clinical anti-infective assets in our portfolio. Basilea is listed on the SIX Swiss Exchange (SIX: BSLN). Please visit basilea.com. Disclaimer This communication expressly or implicitly contains certain forward-looking statements, such as "believe", "assume", "expect", "forecast", "project", "may", "could", "might", "will" or similar expressions concerning Basilea Pharmaceutica Ltd, Allschwil and its business, including with respect to the progress, timing and completion of research, development and clinical studies for product candidates. Such statements involve certain known and unknown risks, uncertainties and other factors, which could cause the actual results, financial condition, performance or achievements of Basilea Pharmaceutica Ltd, Allschwil, to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Basilea Pharmaceutica Ltd, Allschwil is providing this communication as of this date and does not undertake to update any forward-looking statements contained herein as a result of new information, future events or otherwise. For further information, please contact: Peer Nils Schröder, PhD Head of Corporate Communications & Investor Relations Basilea Pharmaceutica International Ltd, Allschwil Hegenheimermattweg 167b 4123 Allschwil Switzerland Phone +41 61 606 1102 E-mail media_relations@basilea.com investor_relations@basilea.com This press release can be downloaded from . References IQVIA Analytics Link, September 2023. In-market sales reported as moving annual total (MAT) in US dollar. Cresemba US prescribing information: [Accessed: January 4, 2024] ERADICATE (SAB): ClinicalTrials.gov identifier NCT03138733 T. L. Holland, S. E. Cosgrove, S. B. Doernberg et al. Ceftobiprole for treatment of complicated Staphylococcus aureus bacteremia. New England Journal of Medicine 2023 (389), 1390-1401; DOI: 10.1056/NEJMoa2300220 Basilea’s ceftobiprole phase 3 program is funded in part with federal funds from the US Department of Health and Human Services (HHS); Administration for Strategic Preparedness and Response (ASPR); Biomedical Advanced Research and Development Authority (BARDA), under contract number HHSO100201600002C. Basilea has been awarded approximately USD 112 million, or approximately 75 percent of the costs related to the phase 3 studies in SAB and acute bacterial skin and skin structure infections (ABSSSI), regulatory activities and non-clinical work. Research reported in this press release is supported by CARB-X. CARB-X’s funding for the preclinical program on DXR inhibitors is provided in part with federal funds from the US Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority; under agreement number: 75A50122C00028, and by awards from Wellcome (WT224842), Germany’s Federal Ministry of Education and Research (BMBF), the UK Global Antimicrobial Resistance Innovation Fund (GAMRIF) funded by the UK Government Department of Health and Social Care (DHSC), and the Bill & Melinda Gates Foundation. The content of this press release is solely the responsibility of the authors and does not necessarily represent the official views of CARB-X or any of its funders. Attachments Press release (PDF)

临床3期申请上市上市批准并购

100 项与 B1R inhibitors(Alpha-9 Theranostics) 相关的药物交易

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