Lonafarnib

Sentynl, a Zydus Group company, receives worldwide proprietary rights to Zokinvy, adding to portfolio of biopharmaceuticals for rare and ultra-rare diseasesZokinvy is approved in the U.S. (2020), European Union and Great Britain (2022), and Japan (2024) for the treatment of progeria, a collection of ultra-rare, fatal, genetic premature aging diseases that accelerate mortality in young patients SOLANA BEACH, Calif. and AHMEDABAD, India and PALO ALTO, Calif., May 3, 2024 /PRNewswire/ -- Sentynl Therapeutics, Inc. (Sentynl), a U.S.-based biopharmaceutical company wholly-owned by Zydus Lifesciences, Ltd. (Zydus Group), and Eiger BioPharmaceuticals, Inc. (OTC: EIGRQ), a commercial-stage biopharmaceutical company focused on the development of innovative therapies for rare metabolic diseases, today announced the closing of the sale of Eiger's Zokinvy® (lonafarnib) program to Sentynl. Continue Reading Zydus (PRNewsfoto/Sentynl Therapeutics) Eiger BioPharmaceuticals logo Zokinvy is the first and only treatment approved by the U.S. Food and Drug Administration (FDA) to target the cause and symptoms of progeria, also known as Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies (PDPL), in young people 12 months of age and older. Collectively known as progeria, HGPS and PDPL are ultra-rare, fatal, genetic premature aging diseases that accelerate mortality in young patients. Following its U.S. approval in 2020, Zokinvy secured approval in the European Union and Great Britain (2022) and in Japan (January 2024). Speaking on the acquisition, Dr. Sharvil Patel, Managing Director of Zydus Lifesciences, said, "This acquisition marks an important milestone in growing our portfolio of medicines for rare and orphan diseases, which can have devastating consequences if left untreated. We are focused on supporting patients to live healthier and more fulfilled lives. The acquisition of Zokinvy directly furthers this mission, as it has a demonstrated meaningful impact on young patients and their families." "It is an honor to add Zokinvy to our portfolio of products that have a tangible impact on the lives of rare disease patients, whose needs are too often unmet or overlooked," said Matt Heck, President & Chief Executive Officer of Sentynl. "We are firmly committed to provide best-in-class global access to Zokinvy and are eager to serve the patients and their families affected by progeria. We are grateful to Eiger and The Progeria Research Foundation for their dedicated effort to develop and secure availability of this life-changing product." "We are pleased to complete this agreement with Sentynl, given our shared commitment to supporting patients of life-threatening, rare conditions with high unmet medical needs," said David Apelian, MD, PhD, MBA, CEO of Eiger. "We thank The Progeria Research Foundation for their continued support of Zokinvy." Audrey Gordon, President and Executive Director of The Progeria Research Foundation (PRF), added, "Without Zokinvy therapy, children with progeria die of the same heart disease that affects millions of normally aging adults, but by an average age of 14.5 years old. Zokinvy gives these beautiful children longer, healthier lives. Since we first launched PRF in 1999, we have achieved tremendous progress in global awareness, breakthrough research, and treatment of progeria. We are thankful for our successful partnership with Eiger, and are excited to now join forces with Sentynl in our journey to continue advancing the research and treatment of this syndrome, with the ultimate goal to find the cure." As previously disclosed by Eiger, on April 1, 2024, Eiger and its direct subsidiaries filed voluntary petitions for relief under chapter 11 of Title 11 of the United States Code (Chapter 11 Cases) in the United States Bankruptcy Court for the Northern District of Texas (Bankruptcy Court). On April 17, 2024, following the completion of the auction held as part of the Eiger's court-supervised sale process, Sentynl was designated the winning bidder with a final bid during the auction of a base price in the amount of $46.1 million less a credit in the amount of $0.9 million for the termination fee resulting in a net base price in the amount of $45.2 million, subject to certain purchase price adjustments, including a reduction of $100,000 per diem if the sale closed after April 24, 2024. At a hearing held on April 23, 2024, the Bankruptcy Court approved the sale to Sentynl, with the sale closing on May 3, 2024. Under the terms of the acquisition, Sentynl acquired global rights to Zokinvy and will be responsible for its manufacture and commercialization. For questions on continued access to Zokinvy, please contact the Sentynl Cares support team at 1-888-251-2800 Monday-Friday, 8 am-8 pm ET. For inquiries after hours, follow the recorded instructions. About Progeria Collectively known as progeria, Hutchinson-Gilford progeria syndrome and progeroid laminopathies are ultra-rare, fatal, genetic premature aging diseases that accelerate mortality in young patients. HGPS is caused by a point mutation in the LMNA gene, yielding the farnesylated aberrant protein, progerin. Progeroid laminopathies are genetic conditions of accelerated aging caused by a constellation of mutations in the LMNA and/or ZMPSTE24 genes yielding farnesylated proteins that are distinct from progerin.4,5 Without Zokinvy therapy, children with HGPS commonly die of the same heart disease that affects millions of normally aging adults (arteriosclerosis), by an average age of 14.5 years. Disease manifestations include severe failure to thrive, scleroderma–like skin, global lipodystrophy, alopecia, joint contractures, skeletal dysplasia, global accelerated atherosclerosis with cardiovascular decline, and debilitating strokes.3 About Zokinvy (lonafarnib) Zokinvy is a first-in-class disease-modifying agent that blocks the accumulation of defective progerin and progerin-like proteins which leads to cellular instability and premature aging in children and young adults with progeria. Zokinvy has demonstrated a statistically significant survival benefit in children and young adults with HGPS.1,4 The most commonly reported adverse reactions were gastrointestinal (vomiting, diarrhea, nausea), and most were mild or moderate (Grade 1 or 2) in severity. Many progeria patients have received continuous Zokinvy therapy for more than 10 years.1,2 Zokinvy is FDA approved for the treatment of patients 12 months of age and older with a genetically confirmed diagnosis of Hutchinson-Gilford progeria syndrome or a processing-deficient progeroid laminopathy associated with either a heterozygous LMNA mutation with progerin-like protein accumulation or a homozygous or compound heterozygous ZMPSTE24 mutation. For Important Safety Information and prescribing information for Zokinvy in the U.S., please visit . Eiger licensed exclusive worldwide rights to lonafarnib for the treatment of H-G progeria from MSD, the tradename of Merck & Co., Inc, Rahway, N.J., USA. MSD provided lonafarnib free of charge for clinical studies supported by the PRF and waived royalty and milestone obligations on lonafarnib from Sentynl for people living with the condition. Eiger and AnGes entered into an exclusive distribution agreement for the treatment of HGPS and PDPL indications, Zokinvy (Lonafarnib), in Japan on May 10, 2022. In March 2023, the Ministry of Health, Labour and Welfare designated Zokinvy as an orphan drug. About Sentynl Therapeutics Sentynl Therapeutics is a U.S.-based biopharmaceutical company focused on bringing innovative therapies to patients living with rare diseases. The company was acquired by the Zydus Group in 2017. Sentynl's experienced management team has previously built multiple successful pharmaceutical companies. With a focus on commercialization, Sentynl looks to source effective and well-differentiated products across a broad spectrum of therapeutic areas to address unmet needs. Sentynl is committed to the highest ethical standards and compliance with all applicable laws, regulations and industry guidelines. For more information, visit . About Zydus Group Zydus Lifesciences Ltd. with an overarching purpose of empowering people with freedom to live healthier and more fulfilled lives, is an innovative, global lifesciences company that discovers, develops, manufactures, and markets a broad range of healthcare therapies. The group has a significant presence in cancer related therapies and offers a wide range of solutions with cytotoxic, supportive & targeted drugs. The group employs over 26,000 people worldwide, including 1,400 scientists engaged in R & D, and is driven by its mission to unlock new possibilities in lifesciences through quality healthcare solutions that impact lives. The group aspires to transform lives through path-breaking discoveries. For more information, visit . About Eiger Biopharmaceuticals Eiger is a commercial-stage biopharmaceutical company focused on the development of innovative therapies for rare metabolic diseases. Eiger's lead product candidate, avexitide, is a well characterized, first-in-class GLP-1 antagonist for the treatment of post-bariatric hypoglycemia (PBH) and congenital hyperinsulinism (HI). Avexitide is the only drug in development for PBH with Breakthrough Therapy designation from the FDA. On April 1, 2024, Eiger and its direct subsidiaries filed the Chapter 11 Cases in the Bankruptcy Court. Eiger's securityholders are cautioned that trading in Eiger's securities during the pendency of the Chapter 11 Cases is highly speculative and poses substantial risks. Trading prices for Eiger's securities may bear little or no relationship to the actual recovery, if any, by holders thereof in the Chapter 11 Cases. Accordingly, Eiger urges extreme caution with respect to existing and future investments in its securities. In particular, Eiger expects that its securityholders could experience a significant or complete loss on their investment, depending on the outcome of the Chapter 11 Cases. About The Progeria Research Foundation The Progeria Research Foundation (PRF) was established in 1999 by the family of Sam Berns, a child with Progeria. Within four years of its founding, the PRF Genetics Consortium discovered the Progeria gene, a collaboration led by Dr. Francis Collins, Acting Science Advisor to the President of the United States and former Director of the National Institutes of Health (NIH). PRF has funded and co-coordinated all Zokinvy associated clinical trials for Progeria and Progeroid Laminopathies, conducted at Boston Children's Hospital, and supports scientists who conduct Progeria research worldwide. PRF's International Patient Registry includes over 393 children with Progeria in 72 countries. PRF is the only non-profit organization solely dedicated to finding treatments and the cure for Progeria and its aging-related conditions, including heart disease. The organization fills a void, putting these children and Progeria at the forefront of scientific efforts. For more information and to support PRF's mission, please visit . Note Regarding Forward-Looking Statements of Eiger This press release contains forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical facts, including statements regarding the continued commercialization and manufacturing of Zokinvy, the outcome of the Chapter 11 Cases, business strategy and plans and objectives for future operations, are forward-looking statements. Various important factors could cause actual results or events to differ materially from the forward-looking statements that Eiger makes, including additional applicable risks and uncertainties described in the "Risk Factors" section in Eiger's Quarterly Report on Form 10-K for the year ended December 31, 2023, and Eiger's subsequent filings with the SEC. The forward-looking statements contained in this press release are based on information currently available to Eiger and speak only as of the date on which they are made. Eiger does not undertake and specifically disclaims any obligation to update any forward-looking statements, whether as a result of any new information, future events, changed circumstances or otherwise. References: 1. Data on file, Eiger BioPharmaceuticals. 2. Summary of Product Characteristics, July 2022. 3. Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford Progeria Syndrome. 2003 Dec 12 [Updated 2019 Jan 17]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. 4. Gordon LB, Shappell H, Massaro J, et al. Association of lonafarnib treatment vs no treatment with mortality rate in patients with Hutchinson-Gilford progeria syndrome. JAMA. 2018;319(16):1687-1695. doi:10.1001/jama.2018.3264. 5. Marcelot A, Worman HJ, and Zinn-Justin S. Protein structural and mechanistic basis of progeroid laminopathies. FEBS Journal. 2021:288:2757-2772. Doi:10.111/febs.15526. SOURCE Sentynl Therapeutics

▎药明康德内容团队编辑蛋白质脂化修饰是一种至关重要的翻译后修饰（PTM）机制，这一过程受到40余种酶的精确调控，影响着超过1000种蛋白质底物。这种修饰作用对于细胞信号传导、物质转运和功能的维持发挥着核心作用，同时在调节细胞死亡、维护蛋白质稳定性以及其他基本生物学过程中也扮演着关键角色。在癌症的形成和进展中，蛋白质脂质化尤为关键，涵盖了多个方面，包括调控促进肿瘤生长的癌蛋白功能、调节免疫应答及新陈代谢的核心分子。尽管蛋白质脂化对癌症的影响已经得到了广泛认识，但在药物研发领域，这一机制的研究仍处于初步阶段，既面临挑战也蕴藏着巨大潜力。近期，《自然》杂志子刊Nature Reviews Cancer发表了一篇综述文章，深入分析了蛋白质脂化的生物学基础、在癌症中的异常调控，以及其中的潜在药物靶点。在今天的文章里，药明康德内容团队将为读者展示其中的精彩亮点，分享蛋白质脂化在癌症治疗中的前景。蛋白质脂化在癌症病理过程中的作用蛋白质脂化修饰是一种多样化的PTM机制，在多种生物学活动中扮演着关键角色。这种修饰显著提升了蛋白质分子在脂化位点的疏水性，使得蛋白质与细胞膜之间能够建立直接的物理相互作用，从而深刻影响蛋白质的定位、功能和相互作用。蛋白质脂质化大致可以分为两大类：构成性脂化（constitutive lipidation）和动态脂化（dynamic lipidation）。构成性脂化是蛋白质合成或成熟过程中固有的，脂质基团作为蛋白质不可分割的一部分被添加上去；而动态脂化则根据功能需求在成熟蛋白质上动态添加或移除脂质基团。构成性脂化修饰主要包括S-异戊二烯化（包括法尼基化和香叶基香叶酰化修饰）以及N-豆蔻酰化，而动态脂化中最常见的类型是可逆的S-脂酰化。图片来源：药明康德内容团队制图蛋白质脂化及其在癌症中的角色和治疗潜力是当前生物医学研究中的一个热点领域。作为一种PTM机制，蛋白质脂化在肿瘤的形成、进展和免疫调节中的异常调控揭示了众多未被充分挖掘的潜在药物靶点，为癌症治疗药物的开发带来了新希望。其中，与癌症密切相关的脂化蛋白，特别是关键的脂质转移酶和水解酶，由于它们与多种致癌途径的交互作用，成为了具有重大影响力的潜在治疗靶点。尽管这些酶在癌症中的突变并不普遍，但深入探究它们在致癌基因网络中的作用，可能为发现新的治疗策略提供契机。蛋白质的脂化作用主要发生在细胞内部，这一过程不仅影响蛋白质的分泌和在细胞表面的分布，还可能影响信号传递和抗癌免疫响应。值得注意的是，脂化蛋白也被发现存在于细胞外囊泡中，这一发现为其作为潜在的癌症生物标志物提供了依据。对于某些特定的分泌蛋白，比如Hedgehog和Wnt信号分子，脂化修饰对其旁分泌信号传递至关重要。鉴于完全抑制脂化途径可能产生不利影响，药物开发的策略应侧重于识别能够提供有效治疗且具有良好治疗指数的药物，这些药物可能单独使用或与其他疗法结合，以期获得更优的治疗效果。源自蛋白质脂化过程的新兴抗癌靶点 与S-异戊二烯化相关的潜在靶点S-异戊二烯化是一种发生在蛋白质合成后的快速且不可逆的过程，这种修饰持续存在于蛋白质的整个生命周期。这一过程由四种主要的蛋白质异戊二烯化转移酶催化——包括法尼基转移酶（FTase）和三种香叶基香叶酰化转移酶（GGTases I、II和III）。这些酶将异戊二烯基脂质基团附加到蛋白质C末端或其附近的半胱氨酸残基上，从而启动了S-异戊二烯化修饰过程。法尼基转移酶异戊二烯化过程在多种癌症蛋白的调控中扮演了重要角色，尤其是在四种RAS异构体（KRAS4A，KRAS4B，NRAS和HRAS）中。这些RAS蛋白在大约19%的癌症患者中出现突变，通常与治疗耐药性有关。例如，NRAS的激活性突变与黑色素瘤和某些类型的白血病相关联；KRAS突变则普遍见于胰腺癌和肺癌中；HRAS突变则与特定的头颈癌和急性髓系白血病（AML）相关。异戊二烯化通过调节这些癌蛋白的膜定位和信号传导，对它们的功能产生重要影响。针对这些RAS突变及其他异戊二烯化蛋白的治疗策略正在积极研究中。例如，抑制法尼基转移酶可能导致KRAS和NRAS从法尼基化转向由香叶基香叶酰化转移酶I介导的香叶基香叶酰化，这种转变可以恢复RAS蛋白的功能。化学蛋白质组学研究揭示，这种转变仅发生在少数FTase底物，揭示其机制可能有助于发现新的治疗策略和癌症生物标志物。2020年，Zokinvy作为针对蛋白质脂质转移酶的首个药物获得批准，展示了选择性地调节蛋白质脂化修饰来扩大法尼基转移酶抑制剂治疗指数的可能性。此外，由于HRAS蛋白仅通过FTase进行异戊二烯化，FTase抑制剂（FTIs）的使用可以特异性地阻断这一过程。近期研究重点放在使用FTIs治疗带有HRAS突变的头颈部鳞状细胞癌（HNSCC）和AML。此外，FTIs与酪氨酸激酶抑制剂、KRAS G12C抑制剂、PI3Kα抑制剂和EGFR抑制剂等其他靶向药物的联合使用正在探索中，这些联合疗法策略在克服耐药性和防止癌症复发方面显示出潜在的优势，且未观察到显著的毒性。这些研究表明，FTIs可能不仅对RAS异构体，也对其他FTase底物具有治疗潜力。图片来源：123RF靶向异戊二烯生物合成过程抑制异戊二烯生物合成也是一种潜在的癌症治疗策略。他汀类药物通过抑制3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）在胆固醇和异戊二烯生物合成上游发挥作用，但其在癌症治疗中的具体效果还未明确。另一方面，双膦酸类药物（如唑来膦酸）在乳腺癌的辅助治疗中显示出了潜力，这是因为它们能够针对破骨细胞中的异戊二烯二磷酸生物合成过程，从而有助于减少治疗后的转移和复发风险。具有亲脂性的双膦酸类药物具有更广泛的组织分布，并已显示出抑制RAS活性的能力。这类药物与雷帕霉素联用在KRAS驱动的小鼠肺腺癌模型中表现出了治疗效果。因此，进行前瞻性临床试验来明确将异戊二烯生物合成作为癌症一线治疗靶点的可行性是十分必要的。      与N-豆蔻酰化相关的潜在靶点N-肉豆蔻酰转移酶（NMT）N-肉豆蔻酰化是一种不可逆的C14:0脂化修饰，由NMT催化，作用于人类蛋白质组中200多种底物蛋白的N-末端甘氨酸上。在哺乳动物中存在两种NMT编码基因，即NMT1和NMT2，这两者在催化区域高度保守。当前研究表明，NMT1在大部分细胞中贡献了超过80%的NMT活性，而NMT2的特异性底物尚未被发现。因此，NMT1被认为是在癌细胞系中的核心必需基因。肉豆蔻酰化作用可促进蛋白质与细胞膜的动态结合，引发诸如S-酰基化等继发性PTM以及蛋白质间的相互作用，影响蛋白质复合体的酶活性或对可溶性蛋白质进行异构调控。NMT活性是癌症治疗中的一个重要干预点，因其能够影响多个难以靶向的癌蛋白。研究显示，抑制NMT可在肿瘤细胞中引发“氨基酸饥饿”反应，阻碍蛋白质合成，这一作用对于蛋白质翻译率较高的癌症尤其有效。此外，NMT抑制剂（NMTi）可能通过抑制ARF和ARL蛋白的功能，在敏感性癌细胞中引发内质网应激，这为多种癌症提供了治疗机会。NMTi通过消除ARF1蛋白肉豆蔻酰化诱导的未折叠蛋白反应（UPR），选择性地清除由化疗或致癌转化产生的衰老细胞。尽管NMT1和NMT2并未直接与癌症相关的突变有关，但研究显示NMT1的表达增加与癌症的进展以及乳腺癌和其他癌症的不良预后有关。目前并未发现NMT2的表达与癌症的严重程度或预后直接相关，虽然在某些血液细胞系和癌症中其表达趋于下降。NMT底物蛋白SRC家族激酶是最早被发现的NMT底物之一。随后的研究揭示，NMT能够调节涉及多个致癌途径的底物蛋白。这些NMT底物包括一些传统上难以作为药物靶点的致癌蛋白家族，例如ADP-核糖化因子蛋白（ARFs）、ARF样蛋白（ARLs），以及参与高尔基体重组与堆积的蛋白（GORASP）。图片来源：药明康德内容团队制图靶向肉豆蔻酰化的其他药理学途径针对豆蔻酰化的药理学策略展示了在癌症治疗领域的新兴途径。例如，BCR-ABL蛋白是伊马替尼的主要作用靶点，然而由于伊马替尼对ABL激酶的选择性不足，导致耐药性和毒性问题，这限制了其临床治疗效果的持续性。Asciminib是一种新型药物，通过靶向BCR-ABL的肉豆蔻酰结合位点，恢复其抑制作用，进而使BCR-ABL失活。2021年，asciminib获得FDA批准，成为首个靶向N-肉豆蔻酰化修饰的药物。此外，选择性诱导铁死亡作为癌症治疗的一个研究热点，展示了肉豆蔻酰化修饰在调节FSP1蛋白相分离中的作用，这种机制可通过药物干预激发铁死亡，对于GPX4功能缺失的黑素瘤和肺癌异种移植模型展现出了抗肿瘤活性。研究表明，ACBD6和ACSL1这两种蛋白在肉豆蔻酰辅酶A的运输与代谢过程中发挥着至关重要的作用，这一发现可能与某些癌症的发展机制密切相关。为了有效利用这一机制作为治疗靶点，有必要深入探究癌细胞如何调控脂质辅酶A的生物合成过程。此外，研究还指出，通过干预N-肉豆蔻酰化蛋白的分子伴侣，比如UNC119同源物，可以间接地调节N-肉豆蔻酰化过程。然而，针对UNC119的当前抑制剂在调控致癌信号传导方面的效果尚有限，这表明需要进一步研究和开发更有效的分子工具和药物策略。图片来源：123RF      与S-棕榈酰化相关的潜在靶点在人类中，S-棕榈酰化是一种由ZDHHC家族的23种蛋白所催化的可逆脂质修饰过程。棕榈酰基团的去除则由多种酰基蛋白硫酯酶（APT）催化，其中包括APT1、APT2及包含ABHD结构域的蛋白。虽然ZDHHC蛋白催化了大多数棕榈酰化事件，但它如何与APT蛋白相互作用以招募特定底物的机制目前还未完全阐明。目前已知超过2400种哺乳动物蛋白经历棕榈酰化，这些蛋白覆盖了广泛的功能类别，其中包括超过150种与癌症相关的致癌蛋白。转录增强相关结构域（TEAD）蛋白TEAD蛋白是通过Hippo信号通路调控细胞生长与增殖的关键因子，其棕榈酰化对于保持蛋白质稳定性、与YAP/TAZ蛋白的相互作用、以及转录活性至关重要。YAP/TAZ与TEAD的过度激活在多种实体肿瘤中被观察到，促进了开发能够结合TEAD棕榈酸口袋并破坏YAP/TAZ与TEAD之间相互作用的抑制剂。例如GNE-7883，这是一种TEAD棕榈酰化抑制剂，能强效抑制YAP/TAZ与所有TEAD家族成员的结合，并在非小细胞肺癌模型中逆转了对KRAS G12C抑制剂的耐药性。TEAD棕榈酰化抑制剂在针对间皮瘤的临床试验中展现了良好的耐受性和抗肿瘤活性。图片来源：123RFSTAT3作为一种促炎和促肿瘤的转录因子，其棕榈酰化和去棕榈酰化循环受到ZDHHC7、ZDHHC3和APT2的调控。棕榈酰化作用使STAT3定位至质膜，在此处被JAK2磷酸化，随后通过APT2催化的去棕榈酰化促使磷酸化的STAT3转移到细胞核内，激活目标基因的表达。ZDHHC7的敲除或通过小分子抑制剂抑制APT2及其相关的棕榈酰化作用能够抑制STAT3的激活，为STAT3依赖性癌症的治疗提供了新靶点。值得注意的是，不同组织中调控STAT3及其上游棕榈酰化信号蛋白的ZDHHC蛋白可能存在差异，这为实现组织特异性的调控提供了可能。ZDHHC在癌症免疫治疗中，蛋白棕榈酰化作用展现出了潜在的重要作用，尤其是在调节免疫检查点蛋白（如PD-L1和PD-1）的功能方面。这些蛋白的棕榈酰化过程主要由ZDHHC3和ZDHHC9酶催化，该过程可以阻止它们被泛素化和降解，从而影响免疫检查点的功能。不过，这一机制在T细胞环境中的效应还需进一步的实验验证。最近的一项研究通过在体内抑制ZDHHC20的活性，揭示了其在胰腺导管腺癌（PDAC）小鼠模型中促进转移性生长的关键作用。研究发现，ZDHHC20的活性仅与肿瘤的转移有关，而对细胞的存活能力或原发性肿瘤的生长并无显著影响。该机制可能涉及到通过棕榈酰化作用调节细胞表面受体，从而抑制肿瘤微环境中的先天免疫反应。值得注意的是，虽然ZDHHC20基因敲除的小鼠的存活和生育能力与正常小鼠无异，但在PDAC患者中观察到ZDHHC20的高表达水平与较差的生存预后相关联。因此，开发ZDHHC20抑制剂可能成为一种新的治疗策略。此外，干扰素（IFNs）在调节机体对抗肿瘤细胞的免疫反应中扮演着关键角色，其中IFNα作为癌症治疗的一部分已得到FDA的批准。在某些对免疫治疗产生耐药的患者中，观察到对IFNγ应答较弱，这一现象与IFNγ受体IFNGR1的加速降解有关。IFNGR1的棕榈酰化过程促进了其向溶酶体的运输和随后的降解。有研究表明，通过使用非特异性脂质生物合成抑制剂如丝裂霉素稳定IFNGR1，可以增强肿瘤的免疫反应，使肿瘤细胞对免疫治疗更加敏感。这些发现为癌症免疫治疗提供了新的潜在策略，突显了深入研究蛋白质棕榈酰化在肿瘤免疫调控中作用的重要性。      与分泌性蛋白脂化相关的潜在靶点形态发生素蛋白Wnt和Hh在胚胎发育及成人干细胞生态位的维持中起关键作用。这些分泌性蛋白需通过膜结合O-乙酰转移酶（MBOATs）进行脂化修饰才能进行分泌或信号传导。具体而言，Wnt家族由PORCN酶在保守型丝氨酸位点进行脂化修饰，而Hh家族在去除内质网信号肽后由HHAT酶在N-末端进行棕榈酰化，并在C-末端进行自催化的胆固醇化。这些形态发生素蛋白与MBOAT酶的关系高度特异，为通过抑制PORCN或HHAT特异性地靶向Wnt或Hh信号传导提供了可能。Wnt和Hh信号通常协同作用以维持癌症干细胞的活性，这在结直肠癌、胰腺导管腺癌和基底细胞癌中扮演着显著的角色。PORCN酶PORCN抑制剂（PORCNi）已经进入临床试验十年之久，但由于长期使用可能导致的骨密度降低等副作用，以及疗效尚不明确，它们还未成为癌症治疗的常规手段。Wnt信号通路被认为能通过排除肿瘤微环境中的T细胞来促进免疫抑制。一些研究表明，PORCNi可能改变免疫特征，从而支持其与抗PD-1检查点抑制剂的联合使用，目前相关的1期和2期临床试验正在进行中。最近报道的PORCN酶及其与WNT974复合物的结构为设计更具选择性的PORCNi开辟了新途径。在Hh信号通路中，Hh配体的N-棕榈酰化对于其在细胞外的分布和与受体PTCH1的结合至关重要，这一过程进而影响下游SMO的激活以及通过GLI转录因子进行的促存活信号传导。目前，尚未发现Hh的N-棕榈酰基水解酶，因此，预计HHAT抑制剂只影响三种Hh配体与PTCH1的结合，HHAT抑制剂很可能比PORCNi更具选择性和针对性。HHAT酶2021年，研究人员通过冷冻电子显微镜首次解析了HHAT的三维结构，揭示了其十次跨膜折叠构象和活性位点的细节，为HHAT抑制剂的开发提供了重要的结构基础。这些研究成果强调了HHAT在特异性地催化Hh配体脂化修饰中的作用，而非参与其他脂质的运输过程。此外，最近开发的Acyl-cLIP技术，一种基于酰基偶联的亲脂性极化诱导的检测方法，为高通量筛选出更具选择性的HHAT抑制剂提供了可能，为临床抗癌靶点的验证提供了工具。图片来源：123RF结语蛋白质脂质化在癌症的发展中扮演了关键角色，近期研究的进展为开发新的治疗策略带来了前所未有的机遇。特别是，直接靶向蛋白质脂质化位点及其相互作用位点已成为研究的重点领域，其中新一代的蛋白质脂质化抑制剂在研究中展现出了显著的效力与选择性。值得一提的是，2020年11月，法尼基转移酶抑制剂lonafarnib（商品名：Zokinvy）获批用于治疗早老症，凸显了蛋白质脂化作为治疗靶点的可行性。深入了解蛋白质脂化失调在癌症中的作用，特别是通过开发新的分析手段以检测和量化蛋白质脂化修饰的变化，对于精准制定治疗方案至关重要。结合蛋白质脂化抑制剂与特定的靶向疗法，有望在可接受剂量下实现持久且稳定的治疗效果。▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Tate, E.W., Soday, L., de la Lastra, A.L. et al. Protein lipidation in cancer: mechanisms, dysregulation and emerging drug targets. Nat Rev Cancer (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41568-024-00666-x免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。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。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新