AbstractNod-like receptor family pyrin-containing protein 3 (NLRP3) inflammasome plays a pathologic role in metabolic dysfunction-associated steatohepatitis (MASH), but the molecular mechanism regulating the NLRP3 inflammasome activation in hepatocellular lipotoxicity remains largely unknown. Bromodomain-containing protein 4 (BRD4) has emerged as a key epigenetic reader of acetylated lysine residues in enhancer regions that control the transcription of key genes. The aim of this study is to investigate if and how BRD4 regulated the NLRP3 inflammasome activation and pyroptosis in MASH. Using the AML12 and primary mouse hepatocytes stimulated by palmitic acid (PA) as an in vitro model of hepatocellular lipotoxicity, we found that targeting BRD4 by genetic knockdown or a selective BRD4 inhibitor MS417 protected against hepatosteatosis; and this protective effect was attributed to inhibiting the activation of NLRP3 inflammasome and reducing the expression of Caspase-1, gasdermin D (GSDMD), interleukin (IL)-1β and IL-6. Moreover, BRD4 inhibition limited the voltage-dependent anion channel-1 (VDAC1) expression and oligomerization in PA-treated AML12 hepatocytes, thereby suppressing the NLRP3 inflammasome activation. Additionally, the expression of BRD4 enhanced in MASH livers of humans. Mechanistically, BRD4 was upregulated during hepatocellular lipotoxicity that in turn modulated the active epigenetic mark H3K27ac at the promoter regions of the Vdac and Gsdmd genes, thereby enhancing the expression of VDAC and GSDMD. Altogether, our data provide novel insights into epigenetic mechanisms underlying BRD4 activating the NLRP3 inflammasome and promoting GSDMD-mediated pyroptosis in hepatocellular lipotoxicity. Thus, BRD4 might serve as a novel therapeutic target for the treatment of MASH.Graphic abstract

2024-12-01·Bioorganic & Medicinal Chemistry

Enhancing therapeutic efficacy in homologous recombination-proficient pancreatic cancer via the combination of PARP1-PROTAC and a BRD4 inhibitor

Article

作者: Liu, Lvye ; Lan, Suke ; Pu, Chunlan ; Liu, Jianyu ; Guo, Yuanbiao ; Liu, Yuanyuan ; Fan, Hengrui

Currently, poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved by U.S. Food and Drug Administration for BRCA-mutated pancreatic cancer therapy. However, limited indications hinder their further application. Repression of bromodomain-containing protein 4 (BRD4) can block the homologous recombination (HR) repair pathway and has the potential to enhance the response to PARPi in HR-proficient pancreatic cancer therapy. In addition, proteolysis targeting chimeras (PROTACs) can hijack E3 ligase within the cell to ubiquitinate degradation-targeted proteins effectively and quickly, thus enhancing the therapeutic effect on tumors. In the present study, the LB23 compound, which induces PARP1 degradation, was employed in combination with the BRD4 inhibitor JQ1, confirming their synergistic effect in HR-proficient pancreatic cancer through various methods. Moreover, compared to the JQ1 and PARPi olaparib combination, PARP1-PROTAC and JQ1 had more notable synergistic effects. Further research into the synergistic mechanism demonstrated that combination therapy enhanced DNA damage and suppressed DNA repair by inducing cell cycle arrest and cell apoptosis. The present study therefore provides the experimental data for this type of combination therapy, which is expected to be an innovative approach for the treatment of HR-proficient pancreatic cancer.

2024-12-01·European Journal of Medicinal Chemistry

Exploration of the tunability of BRD4 degradation by DCAF16 trans-labelling covalent glues

Article

作者: Jin, Cyrus Y ; Qi, Jun ; Ma, Michelle W ; Hassan, Muhammad Murtaza ; Sandoval, Brittany ; Lumpkin, Ryan ; Puvar, Kedar ; Rutter, Justine C. ; Schmoker, Anna M ; Gray, Nathanael S ; Schmoker, Anna M. ; Fischer, Eric S ; Groendyke, Brian J. ; Byun, Woong Sub ; Ebert, Benjamin L. ; Li, Yen-Der ; Ebert, Benjamin L ; Cheong, Hakyung ; Groendyke, Brian J ; Xu, Shawn ; Jin, Cyrus Y. ; Teng, Mingxing ; Gray, Nathanael S. ; Ma, Michelle W. ; Fischer, Eric S. ; Wang, Michelle Y. ; Wang, Michelle Y ; Rutter, Justine C

Chemically induced proximity modalities such as targeted protein degradation (TPD) hold promise for expanding the number of proteins that can be manipulated pharmacologically. However, current TPD strategies are often limited to proteins with preexisting ligands. Molecular glues (e.g. glutarimide ligands for CUL4^CRBN), offer the potential to target undruggable proteins. Yet, their rational design is largely unattainable due to the unpredictability of the 'gain-of-function' nature of the glue interaction upon chemical modification of ligands. We recently reported a covalent trans-labelling glue mechanism which we named 'Template-assisted covalent modification', where an electrophile decorated BRD4 inhibitor was effectively delivered to a cysteine residue on DCAF16 due to an electrophile-induced BRD4-DCAF16 interaction. Herein, we report our efforts to evaluate how various electrophilic modifications to the BRD4 binder, JQ1, affect DCAF16 recruitment and subsequent BRD4 degradation efficiency. We discovered a moderate correlation between the electrophile-induced BRD4-DCAF16 ternary complex formation and BRD4 degradation. Moreover, we show that a more solvent-exposed warhead presentation optimally recruits DCAF16 and promotes BRD4 degradation. The diversity of covalent attachments in this class of BRD4 degraders suggests a high tolerance and tunability for the BRD4-DCAF16 interaction. This offers a new avenue for rational glue design by introducing covalent warheads to known binders.

项与 BRD4 inhibitor (Kainos Medicine, Inc.) 相关的新闻（医药）

2023-08-21

·PRNewswire

Inhalis Therapeutics SA Achieves Key Milestone with Patent Application Filing

LUGANO, Switzerland, Aug. 21, 2023 /PRNewswire/ -- Inhalis Therapeutics SA, a pioneering privately-held company specializing in advanced inhaled treatments for life-threatening diseases, proudly reveals a significant stride forward as it submits a new patent application on INHAL-101, its lead asset. This strategic move strengthens the company's positioning and enriches its intellectual property portfolio. Dr. Silvia Panigone, CEO of Inhalis Therapeutics, expressed her enthusiasm, stating, "The achievement of this pivotal milestone marks a moment of great pride for Inhalis. Our dedicated team has been steadfastly committed to developing INHAL-101, a unique small-molecule PI3K/mTOR/BRD4 tri-specific inhibitor. This ground-breaking formulation employs proprietary mSAS® supercritical fluid technology, demonstrating a compelling profile for addressing the complex challenges of Idiopathic Pulmonary Fibrosis (IPF). By selectively inhibiting the key IPF-driven pathogenic elements through a single inhalable medication, with excellent safety potential, INHAL-101 offers an opportunity to harness its full pharmacological power to be an efficacious and well-tolerated drug. This recent patent application strengthens our competitive positioning and provides additional value for Inhalis. We remain dedicated to our journey, and most importantly, to those people afflicted by IPF who stand to benefit from our unwavering commitment." About Inhalis Therapeutics SA Inhalis Therapeutics SA is committed to develop breakthrough inhaled treatments for life-threatening disorders. Solid science and industry-leading delivery technology are combined with an experienced management team to research and develop new inhaled treatments for Idiopathic Pulmonary Fibrosis and other diseases. The lead asset, INHAL-101, a ground-breaking solution for IPF, is poised to initiate clinical trials in Q4/2024. The company's pipeline also includes INHAL-102, tailored for lung cancer, and additional assets in late-preclinical proof-of-concept stages for oncology, fibrotic diseases and pulmonary infections. For further information, please contact: Silvia Panigone, PhD, EMBA Chief Executive Officer Inhalis Therapeutics SA Phone: +41 78 89 89 644 Email: [email protected] Logo - SOURCE Inhalis Therapeutics SA

2023-02-15

·佰傲谷BioValley

超越PROTAC，又一国产蛋白降解药申报IND

今日（2月15日），根据CDE官网公示，珃诺生物医药科技（杭州）有限公司已经向NMPA提交了该公司注射用RNK05047的IND（新药临床申请），并获得了受理。目前RNK05047已经在国外开展一项临床（NCT05487170），适应症为晚期实体瘤及弥漫性大B细胞淋巴瘤。RNK05047的机理机制RNK05047一款选择性靶向BRD4的FIC蛋白质降解剂，基于该公司的CHAMP™平台开发，这项技术利用了与其他目标蛋白质降解（TPD）方法不同的潜在生物过程，并具有许多独特的优势，包括由于选择性靶向肿瘤而提高的安全性。珃诺生物在2021年美国癌症研究协会年会上发表的海报展示了其具体机制：HSP90伴侣蛋白介导许多重要客户蛋白和突变癌蛋白的折叠，但也可以引导其底物被泛素-蛋白酶体系统降解。此外，在肿瘤组织中，相对于正常组织，HSP90复合物处于高度激活状态，这导致与HSP90结合的小分子化合物显示出独特的肿瘤选择性药代动力学。为了利用HSP90的这些属性以肿瘤选择性的方式降解转录因子BRD4，合成了异双功能小分子化合物，称为伴侣介导的蛋白质降解物(CHAMPs)，其化学诱导BRD4和HSP90之间的接近性。在体外，用BRD4-CHAMP化合物处理MV-4-11白血病细胞可形成BRD4-CHAMP-HSP90三元复合体，随后的蛋白酶体依赖性BRD4降解和细胞增殖抑制。CHAMPs被鉴定为诱导BRD4的选择性降解，并且仅对其他HSP90调节的客户端蛋白显示出最小的影响。虽然BRD4是已知的HSP90客户蛋白，但非HSP90客户蛋白，如突变的KRAS，也可以使用这种方法降解。在体内，在M-小鼠异种移植模型中，具有选择性BRD4-CHAMP化合物在肿瘤中表现出较长时间的药代动力学，与血浆和正常组织相比，其肿瘤浓度在单次给药后至少7天保持高于体外细胞毒性Gl50值。这使得肿瘤中BRD4的90%以上降解并延长，以及BRD4调控的MYC基因的表达降低。在MTD时使用BRD4-CHAMP治疗，单次给药后肿瘤显著消退，大多数肿瘤在3周给药后无法检测到。相比之下，每日给药的临床阶段泛bet抑制剂MTD导致疾病稳定至进展，这表明BRD4-CHAMP在该模型中有显著改善的治疗指数。CHAMP技术相对于其他靶向蛋白降解方法(如PROTAC)具有许多优势，包括由于在肿瘤组织中选择性积累而提高的安全边际。参考来源：http://www.ranoktherapeutics.com/近期热门视频更多精彩视频，尽在佰傲谷视频号，欢迎关注~本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀‍ 点亮在看，传递信息♥

蛋白降解靶向嵌合体临床申请

2022-08-01

·PRNewswire

BridGene Biosciences names David Sperandio, Ph.D., as Head of Chemistry

SAN JOSE, Calif., Aug. 1, 2022 /PRNewswire/ -- BridGene Biosciences, Inc., a biotechnology company using a proprietary chemoproteomics technology to discover and develop small molecules for high value, traditionally undruggable targets, today announced that David Sperandio, Ph.D., a medicinal chemist with more than 20 years' experience, has joined the company as the Head of Chemistry. Dr. Sperandio, an inventor on 23 patents and author of 25 peer-reviewed publications, has extensive experience leading cross-functional teams from molecule discovery through IND filing. Dr. Sperandio will lead the BridGene chemistry team and supervise research into covalent chemistry, chemical proteomics and quantitative mass spectrometry as methods for identifying undruggable targets. Additionally, Dr. Sperandio will be responsible for advancing BridGene's internal pipeline of first-in-class drugs for hard-to-drug targets in oncology. BridGene co-founder and CEO Ping Cao, Ph.D., commented, "David's addition to our leadership team and the recent Series B financing deepen BridGene's capabilities for using IMTAC™ to discover new drugs for novel and traditionally undruggable targets. David's leadership and experience will help expand BridGene's library of molecules to identify as potential drug candidates as we aim to advance a pipeline of first-in-class drugs for these new targets." Dr. Sperandio most recently served as an Executive Director at Biomea Fusion, where he led the team that identified BMF-500, a potential best-in-class targeted covalent FLT-3 inhibitor for the treatment of acute myeloid leukemia. Prior to joining Biomea Fusion, Sperandio led a collaboration of R2M Pharma Inc. with Tenaya Therapeutics Inc., which discovered novel HDAC6 inhibitors for cardiovascular diseases and was key for the clinical development of TN-301, an experimental treatment for heart failure. Dr. Sperandio started his career at Celera Corp. and focused on the structure-guided discovery of covalent reversible serine-protease inhibitors. He later moved to Gilead Sciences Inc., where he led the chemistry team that discovered Alobresib (GS-5829), a novel BRD4 inhibitor for prostate cancer, and Presatorvir (GS-5806), the first small molecule RSV fusion inhibitor that reached the clinic and showed proof of concept in men. Dr. Sperandio commented, "I am excited to join BridGene at such a dynamic time for the company. 2022 has been a remarkable year so far, and I look forward to working closely with the management team to continue to drive the success of IMTAC™." Dr. Sperandio obtained his doctoral degree in Organic Chemistry from the University of Zurich and completed his postdoctoral research at Stanford University. 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 chemoproteomics platform, IMTAC™, BridGene can screen small molecules against proteins in live cells to discover drug candidates for high value and traditionally undruggable targets. For this purpose, BridGene takes advantage of its proprietary, diverse library of tagged, drug-like small molecules. The ultimate goal is to enable breakthrough small molecule drug discovery with expanded mechanisms to treat diseases with targets previously inaccessible to small molecules. The uniqueness of BridGene's technology allows it to perform IMTAC™ screening for both covalent and non-covalent molecules, target different amino acids and discover new targets for disease treatments by deconvoluting phenotypic screening hits. The company 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. Investors Jonathan Nugent +1-205-566-3026 [email protected] Media Bill Borden +1-732-910-1620 [email protected] Dave Schemelia +1-609-468-9325 [email protected] SOURCE BridGene Biosciences

合作First in Class小分子药物

100 项与 BRD4 inhibitor (Kainos Medicine, Inc.) 相关的药物交易

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