Nelfinavir Mesylate

在肿瘤发生发展过程中，抑癌基因启动子区的CpG岛常发生异常高甲基化修饰，进而通过招募DNA甲基化阅读器以强化转录沉默，导致细胞增殖失控并促进肿瘤进展。因此，靶向DNA甲基化阅读器以逆转基因沉默成为当前癌症治疗领域备受关注的研究方向。在多种DNA甲基化阅读器中，甲基化CpG结合域（MBD）蛋白家族发挥着关键作用。其中，MBD2不仅是核小体重塑和组蛋白去乙酰化酶（NuRD）复合体的核心组分，还具有特异性识别甲基化DNA的能力。临床研究表明，MBD2在神经胶质瘤、宫颈癌、胰腺癌等多种人类恶性肿瘤中普遍呈现高表达状态，且其表达水平与肿瘤的生长转移密切相关。然而，MBD2蛋白水平上调与肿瘤发生发展的病理学关联尚未完全阐明，MBD2如何通过整合NuRD复合体来调控肿瘤细胞的表观遗传特征也有待深入研究。近日，复旦大学生物医学研究院温文玉课题组在Nature Cell Biology杂志上发表了题为“Targeting redox-sensitive MBD2–NuRD condensate in cancer cells”的研究论文。该研究揭示了MBD2通过形成相分离凝聚体组装并激活NuRD复合物，进而阻遏抑癌基因转录以促进癌细胞增殖的分子机制，并为MBD2高表达肿瘤提供了基于氧化还原调控的靶向治疗策略。研究团队首先观察到，内源性MBD2蛋白在多种癌细胞的细胞核中呈现明显的点状分布特征，而在正常细胞中这种点状结构显著减小。当以具有促氧化效应的临床药物Elesclomol或Nelfinavir处理肿瘤细胞后，MBD2的分布模式由点状转变为弥散状态，提示肿瘤细胞中高表达的MBD2所形成的点状结构具有氧化还原敏感性。进一步研究发现，MBD2可发生液-液相分离，且只有多甲基化修饰高CG含量的长片段DNA才能显著增强MBD2的相分离能力，这提示在高甲基化CpG岛屿上可能才会发生MBD2的有效凝聚。通过体外酶活实验结合H3K27ac ChIP-seq和ATAC-seq分析，研究证实MBD2相分离凝聚体能够组装并稳定NuRD复合物，显著激活NuRD复合物的去乙酰化酶和染色质重塑活性。在MBD2高表达的癌细胞中，MBD2-NuRD凝聚体特异性靶向异常高甲基化的抑癌基因启动子区域，通过压实染色质结构来抑制转录，从而促进癌细胞增殖。在MBD2相分离突变体（MBD2KRR/E）细胞中，染色质可及性明显增加，抑癌基因表达恢复正常，癌细胞增殖速率显著降低。▲图1 氧化还原敏感的MBD2-NuRD凝聚体调控肿瘤进程（图片来源：原始论文[1]）基于肿瘤细胞中MBD2凝聚体具有氧化还原敏感性这一发现，研究人员筛选确定了MBD2响应氧化还原变化的关键氨基酸位点Cys359。促氧化药物通过氧化Cys359，导致MBD2的氧化还原敏感结构域（RSD）发生去折叠，从而破坏了MBD2凝聚体的形成，最终抑制癌细胞增殖。而在氧化还原敏感突变体（MBD2C359/A）细胞中，促氧化药物抑制肿瘤细胞增殖的效应大大减弱。综上所述，该研究系统阐明了在多种肿瘤中异常高表达的MBD2的作用机制：MBD2通过在肿瘤抑制因子启动子区域高甲基化CpG岛上形成相分离凝聚体，进而组装并激活NuRD复合物，通过组蛋白去乙酰化作用压实染色质结构以抑制转录，促进癌细胞增殖。促氧化剂类抗癌药物可以通过氧化MBD2 C359干扰其相分离，增加染色质开放性，上调抑癌基因表达，从而有效抑制肿瘤生长。这些结果提示，在单个氨基酸精度上特异性干预相分离过程，可能成为针对MBD2相关肿瘤的一种精准医疗策略。复旦大学博士生魏鹤旸为本文的第一作者，复旦大学温文玉研究员为本文的通讯作者。该研究与浙江大学胡荣贵研究员、复旦大学蓝斐研究员合作完成。复旦大学郑洪丹博士生、王司清博士、赵睿倩博士、顾爱红博士，以及国科大杭州高等研究院杨云博士对本文亦有贡献。来源：复旦大学原始论文：[1]Wei, H., Zheng, H., Wang, S. et al. Targeting redox-sensitive MBD2–NuRD condensate in cancer cells. Nat Cell Biol (2025). https://doi.org/10.1038/s41556-025-01657-2欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~

New data includes real-world analyses of VOQUEZNA-treated patients in the U.S. diagnosed with gastroesophageal reflux disease (GERD) FLORHAM PARK, N.J., April 28, 2025 (GLOBE NEWSWIRE) -- Phathom Pharmaceuticals, Inc. (Nasdaq: PHAT), a biopharmaceutical company focused on developing and commercializing novel treatments for gastrointestinal (GI) diseases, today announced that the company will present real-world data for its first-in-class treatment VOQUEZNA® (vonoprazan) at Digestive Disease Week® (DDW) being held May 3–6, 2025, in San Diego, CA. VOQUEZNA is the first and only treatment of its kind approved by the U.S. Food and Drug Administration for use in adults for the relief of heartburn associated with Non-Erosive GERD and for the treatment of all severities of Erosive Esophagitis (EE), commonly referred to as Erosive GERD, and relief of related heartburn. Two Phathom-sponsored posters will be presented on May 5, 2025, at 12:30 p.m. PT in the Poster Hall at the San Diego Convention Center. In addition, Phathom will host a Product Theater highlighting VOQUEZNA as a first-in-class treatment for GERD and will maintain a strong presence throughout the conference at booth #1743 on the exhibit floor. “Millions of GERD patients continue to experience inadequate symptom control despite treatment with proton pump inhibitors (PPIs),” said Eckhard Leifke, M.D., Chief Medical Officer at Phathom. “The data we’re presenting at DDW this year analyze real-world treatment patterns and patient characteristics, offering valuable insights into how VOQUEZNA is being used in clinical practice. These findings suggest VOQUEZNA may play an important role for patients who have not achieved sufficient relief with existing therapies and reinforce Phathom’s commitment to advancing the understanding and management of acid-related GI diseases. We look forward to engaging with healthcare professionals and thought leaders at DDW to further discuss the evolving treatment landscape.” A high-level schedule of Phathom-sponsored activities at DDW 2025 can be found below: Sunday, May 4, 2025 VOQUEZNA® (vonoprazan) Product Theater: Expert Insights on GERD Therapy: A Case-Based Approach with a First-In-Class Acid Suppressant Time: 12:15 – 1:00 pm PTPresenters: Dr. John Erik Pandolfino and Dr. Felice Schnoll-SussmanLocation: DDW Theater 1 Independent Medscape CME Symposia: Clinical Decisions in the Management of GERD: A Patient Simulation Challenge Time: 6:00 – 7:30 pm PTPresenters: Dr. Charles Vega, Dr. Prakesh Gyawali and Dr. Rena YadlapatiIndependent CME sponsored by Phathom Pharmaceuticals Monday, May 5, 2025 Tadataka ‘Tachi’ Yamada, MD, Lecture: Pivotal Role of Acid Suppression: PPIs, PCABs and Beyond in Clinical Practice Time: 8:00 – 9:30 am PTAGA Clinical Symposium sponsored by Phathom Pharmaceuticals Real-World Demographic and Clinical Characteristics of Vonoprazan-Treated Patients in the United States Diagnosed With GERD: A Descriptive Analysis of Non-Erosive vs. Erosive GERD Time: 12:30 pm PTPresentation #: Mo1369Poster Session Real-World Treatment Patterns of Prior Lines of PPI Therapy in Vonoprazan-Treated Patients in the United States Diagnosed with Non-Erosive or Erosive GERD Time: 12:30 pm PTPresentation #: Mo1363Poster Session Following the meeting, data abstracts will be available on Phathom’s publications and scientific congresses section of the company website. VOQUEZNA is marketed exclusively by Phathom Pharmaceuticals, Inc. Please visit VoqueznaPro.com to learn more about VOQUEZNA. About DDWDigestive Disease Week® (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW is an in-person and online meeting from May 3-6, 2025. The meeting showcases more than 5,600 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology. More information can be found at www.ddw.org. INDICATIONS AND USAGE VOQUEZNA® (vonoprazan) is a potassium-competitive acid blocker (PCAB) indicated in adults: for the healing of all grades of Erosive Esophagitis (Erosive Gastroesophageal Reflux Disease or Erosive GERD) and relief of heartburn associated with Erosive GERD.to maintain healing of all grades of Erosive GERD and relief of heartburn associated with Erosive GERD.for the relief of heartburn associated with Non-Erosive GERD.in combination with amoxicillin and clarithromycin for the treatment of Helicobacter pylori (H. pylori) infection.in combination with amoxicillin for the treatment of H. pylori infection. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS VOQUEZNA is contraindicated in patients with a known hypersensitivity to vonoprazan or any component of VOQUEZNA, or in patients receiving rilpivirine-containing products. For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with VOQUEZNA, refer to the Contraindications section of the corresponding prescribing information. WARNINGS AND PRECAUTIONS Presence of Gastric Malignancy: In adults, symptomatic response to therapy with VOQUEZNA does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in patients who have a suboptimal response or an early symptomatic relapse after completing treatment with VOQUEZNA. In older patients, also consider endoscopy. Acute Tubulointerstitial Nephritis: Acute tubulointerstitial nephritis (TIN) has been reported with VOQUEZNA. If suspected, discontinue VOQUEZNA and evaluate patients with suspected acute TIN. Clostridioides difficile-Associated Diarrhea: Published observational studies suggest that proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridioides difficile-associated diarrhea (CDAD), especially in hospitalized patients. VOQUEZNA may also increase the risk of CDAD. Consider CDAD in patients with diarrhea that does not improve. Use the shortest duration of VOQUEZNA appropriate to the condition being treated. CDAD has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with VOQUEZNA, refer to Warnings and Precautions section of the corresponding prescribing information. Bone Fracture: Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine, especially in patients receiving high dose (multiple daily doses) and long-term therapy (a year or longer). Bone fracture, including osteoporosis-related fracture, has also been reported with vonoprazan. Use the shortest duration of VOQUEZNA appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines. Severe Cutaneous Adverse Reactions (SCAR): Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with VOQUEZNA. Discontinue VOQUEZNA at the first signs or symptoms of SCAR or other signs of hypersensitivity and consider further evaluation. Vitamin B12 (Cobalamin) Deficiency: Long-term use of acid-suppressing drugs can lead to malabsorption of Vitamin B12 caused by hypo- or achlorhydria. Vitamin B12 deficiency has been reported postmarketing with vonoprazan. If clinical symptoms consistent with vitamin B12 deficiency are observed in patients treated with VOQUEZNA, consider further workup. Hypomagnesemia and Mineral Metabolism: Hypomagnesemia has been reported postmarketing with vonoprazan. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. Consider monitoring magnesium levels prior to initiation of VOQUEZNA and periodically in patients expected to be on prolonged treatment, in patients taking drugs that may have increased toxicity in the presence of hypomagnesemia or drugs that may cause hypomagnesemia. Treatment of hypomagnesemia may require magnesium replacement and discontinuation of VOQUEZNA. Consider monitoring magnesium and calcium levels prior to initiation of VOQUEZNA and periodically while on treatment in patients with a preexisting risk of hypocalcemia. Supplement with magnesium and/or calcium, as necessary. If hypocalcemia is refractory to treatment, consider discontinuing VOQUEZNA. Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Temporarily discontinue VOQUEZNA treatment at least 4 weeks before assessing CgA levels and consider repeating the test if initial CgA levels are high. Fundic Gland Polyps: Use of VOQUEZNA is associated with a risk of fundic gland polyps that increases with long-term use, especially beyond one year. Fundic gland polyps have been reported with vonoprazan in clinical trials and during postmarketing use with PPIs. Most patients who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of VOQUEZNA appropriate to the condition being treated. ADVERSE REACTIONS: Healing of Erosive GERD: The most common adverse reactions (≥2% of patients in the VOQUEZNA arm) include gastritis (3%), diarrhea (2%), abdominal distention (2%), abdominal pain (2%), and nausea (2%). Maintenance of Healed Erosive GERD: The most common adverse reactions (≥3% of patients in the VOQUEZNA arm) include gastritis (6%), abdominal pain (4%), dyspepsia (4%), hypertension (3%), and urinary tract infection (3%). Relief of Heartburn Associated with Non-Erosive GERD: The most common adverse reactions (≥2% of patients in the VOQUEZNA arm) include abdominal pain (2%), constipation (2%), diarrhea (2%), nausea (2%), and urinary tract infection (2%). Treatment of H. Pylori Infection (VOQUEZNA and Amoxicillin): The most common adverse reactions (≥2% in any treatment arm) include diarrhea (5%), abdominal pain (3%), vulvovaginal candidiasis (2%), nasopharyngitis (2%), dysgeusia (1%), headache (1%), and hypertension (1%). Treatment of H. Pylori Infection (VOQUEZNA, Amoxicillin and Clarithromycin): The most common adverse reactions (≥2% in any treatment arm) include dysgeusia (5%), diarrhea (4%), vulvovaginal candidiasis (3%), headache (3%), abdominal pain (2%), hypertension (2%), and nasopharyngitis (<1%). For more information on adverse reactions and laboratory changes with amoxicillin or clarithromycin, refer to Adverse Reactions section of the corresponding prescribing information. DRUG INTERACTIONS VOQUEZNA has the potential for clinically important drug interactions, including interactions with drugs dependent on gastric pH for absorption, drugs that are substrates for certain CYP enzymes, and some diagnostic tests. Avoid concomitant use of VOQUEZNA with atazanavir or nelfinavir. See full Prescribing Information for more details about important drug interactions. Consult the labeling of concomitantly used drugs to obtain further information about interactions with vonoprazan. For information about drug interactions, contraindications, and warnings and precautions of antibacterial agents (amoxicillin or clarithromycin) indicated in combination with VOQUEZNA, refer to their corresponding prescribing information. USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended during treatment. Because of the potential risk of adverse liver effects shown in animal studies with vonoprazan, advise patients not to breastfeed during treatment with VOQUEZNA. Renal Impairment: For the healing of Erosive GERD, dosage reduction is recommended in patients with severe renal impairment (eGFR < 30 mL/min). Use of VOQUEZNA is not recommended for the treatment of H. pylori infection in patients with severe renal impairment. Hepatic Impairment: For the healing of Erosive GERD, dosage reduction is recommended in patients with moderate to severe hepatic impairment (Child-Pugh Class B and C). Use of VOQUEZNA is not recommended for the treatment of H. pylori infection in patients with moderate to severe hepatic impairment. You are encouraged to report suspected adverse reactions by contacting Phathom Pharmaceuticals at 1-888-775-PHAT (7428) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please click here to see full Prescribing Information for VOQUEZNA. About Gastroesophageal Reflux Disease (GERD) GERD is one of the most prevalent gastrointestinal diseases, with approximately 1 in 5 U.S. adults living with the condition. Depending on the severity, GERD can cause heartburn, regurgitation, difficulty eating and drinking and damage to the esophageal lining. There are two main types of GERD. The largest category of GERD is Non-Erosive GERD, which is characterized by reflux-related symptoms in the absence of esophageal mucosal erosions. It is estimated that approximately 70% of the overall GERD population have Non-Erosive GERD. Symptoms of Non-Erosive GERD may impact overall quality of life and can include episodic heartburn, especially at night, regurgitation, problems swallowing, and chest pain. Erosive GERD, also referred to as Erosive Esophagitis (EE), is a subtype of GERD characterized by erosions in the gastric mucosa caused by acidic reflux of stomach contents into the esophagus. There are estimated to be over 65 million individuals with GERD in the U.S., of which approximately 30% have Erosive GERD. In addition to experiencing troubling symptoms including heartburn, patients with inadequately treated Erosive GERD may progress to more severe diseases including Barrett’s esophagus and esophageal cancer. About VOQUEZNA® VOQUEZNA® (vonoprazan) tablets contain vonoprazan, an oral small molecule potassium-competitive acid blocker (PCAB). PCABs are a novel class of medicines that block acid secretion in the stomach. VOQUEZNA is approved in the U.S. for the treatment of adults with Erosive Esophagitis, also known as Erosive GERD, the relief of heartburn associated with Erosive GERD, the relief of heartburn associated with Non-Erosive GERD, and for the treatment of H. pylori infection in combination with either amoxicillin or amoxicillin and clarithromycin. Phathom in-licensed the U.S. rights to vonoprazan from Takeda, which markets the product in Japan and numerous other countries in Asia and Latin America.  About Phathom Pharmaceuticals, Inc. Phathom Pharmaceuticals is a biopharmaceutical company focused on the development and commercialization of novel treatments for gastrointestinal diseases. Phathom has in-licensed the exclusive rights to vonoprazan, a first-in-class potassium-competitive acid blocker (PCAB) that is currently marketed in the United States as VOQUEZNA® (vonoprazan) tablets for the relief of heartburn associated with Non-Erosive GERD in adults, the healing and maintenance of healing of Erosive GERD in adults and relief of associated heartburn, in addition to VOQUEZNA® TRIPLE PAK® (vonoprazan tablets, amoxicillin capsules, clarithromycin tablets) and VOQUEZNA® DUAL PAK® (vonoprazan tablets, amoxicillin capsules) for the treatment of H. pylori infection in adults. For more information about Phathom, visit the company’s website at www.phathompharma.com and follow on LinkedIn and X. Forward Looking StatementThis press release contains forward-looking statements. Investors are cautioned not to place undue reliance on these forward-looking statements, including statements about the possible treatment role that VOQUEZNA plays for GERD patients, Phathom’s plans to continue to engage with healthcare professions regarding treatment options and estimates of the patient populations with GERD. The inclusion of forward-looking statements should not be regarded as a representation by Phathom that any of its plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in Phathom’s business, including, without limitation: the results of market research regarding real-world usage of VOQUEZNA may not predict acceptance by patients, healthcare providers or payors in the future; we may not be able to successfully commercialize VOQUEZNA, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK, which will depend on a number of factors including coverage and reimbursement levels from governmental authorities and health insurers as well as market acceptance by healthcare providers; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of vonoprazan that may limit its development, regulatory approval and/or commercialization, or may result in recalls or product liability claims; Phathom’s ability to obtain and maintain intellectual property protection and non-patent regulatory exclusivity for vonoprazan; Phathom’s estimates regarding patient population and commercial coverage could prove to be inaccurate; and other risks described in the Company’s prior press releases and the Company’s filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in the Company’s most recent Annual Report on Form 10-K and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Phathom undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. MEDIA CONTACTNick Benedetto1-877-742-8466media@phathompharma.com INVESTOR CONTACTEric Sciorilli1-877-742-8466ir@phathompharma.com © 2025 Phathom Pharmaceuticals. All rights reserved. VOQUEZNA, VOQUEZNA TRIPLE PAK, VOQUEZNA DUAL PAK, Phathom Pharmaceuticals, and their respective logos are registered trademarks of Phathom Pharmaceuticals, Inc.