Down Syndrome

Company licenses novel deep learning-based epigenetic models from CUHK enabling the detection of 5hmC, 5mC hemimethylation, and 6mA in standard sequencing runsMENLO PARK, Calif., April 28, 2025 (GLOBE NEWSWIRE) -- PacBio (Nasdaq: PACB), a leading provider of high-quality, highly accurate sequencing platforms, today announced it plans to improve on its already highly accurate methylation detection capabilities in HiFi chemistry through licensing advanced DNA methylation detection methods developed by Professor Dennis Lo and colleagues at the The Chinese University of Hong Kong (CUHK) and Centre for Novostics. The licensed technology is designed to enhance PacBio HiFi sequencing with improved detection of DNA base modifications—including 5-hydroxymethylcytosine (5hmC) and hemimethylated 5-methylcytosine (5mC)—in native DNA. PacBio plans to bring these capabilities to its Revio and Vega systems, building on its existing 5mC support to deliver even more comprehensive epigenomic insights as part of standard HiFi whole-genome sequencing workflows. “PacBio was the first to detect native epigenetic modifications alongside accurate DNA sequencing. With the integration of the CUHK deep learning models, our technology will be able to detect many additional and biologically meaningful methylation signatures, including 5hmC and strand-specific 5mC,” said Christian Henry, President and CEO of PacBio. "Our commitment to continually improving HiFi chemistry will enable our customers to gain even deeper insights into the human genome, powering new discoveries and clinical possibilities." The newly licensed technology includes an enhanced AI deep learning framework known as Holistic Kinetic Model 2 (HK2), which integrates convolutional and transformer layers to model local and long-range kinetic features with extraordinary precision. HK2 is designed to significantly improve the accuracy of 5mC and N6-methyladenine (6mA) detection and introduces native 5hmC calling in single molecules—a first for HiFi sequencing. HiFi sequencing, available on both the Revio and Vega platforms, provides a comprehensive and simultaneous readout of the genome and epigenome from native DNA without the need for chemical conversion, additional sample preparation, or parallel workflows. The new capabilities from the HK2 model will be delivered to existing customers through software updates, with no changes to sequencing protocols and no additional cost. “I am delighted to see this technology now being deployed more broadly through PacBio’s global customer base,” said Professor Dennis Lo, Scientific Director of Centre for Novostics, CUHK. “Accurate detection of DNA methylation—particularly 5mC and 5hmC—on native molecules is important for advancing research in cancer, human development, and beyond. With the improvements enabled by HK2, methylation calling with PacBio HiFi sequencing is poised to set a new standard for accuracy in the industry, surpassing other available technologies.” CUHK, together with Take2 Technologies Limited, a Hong Kong-based biotechnology company, pioneered robust 5mC detection in 2021 using the PacBio platform. PacBio introduced on-instrument 5mC detection in April 2022 and extended support to 6mA in December 2024 for Fiber-seq chromatin architecture studies. HK2 is designed to push detection performance to new levels of accuracy. Importantly, HK2 will also enable strand-specific 5mC analysis, which opens new opportunities to study hemimethylation—an emerging epigenetic signal. HiFi 5-base sequencing has already been adopted by pioneering institutions such as Children’s Mercy Kansas City, the first to use comprehensive genomic and epigenomic profiling in a clinical setting​. GeneDx is also leveraging this capability to investigate the diagnostic potential of epigenetic signals in neonatal care​. The ability to profile 5hmC—a dynamic and tissue-specific epigenetic mark implicated in brain development, cancer, and neurodegenerative diseases—opens new frontiers in liquid biopsy, cancer detection, and cell-free DNA analysis​. Unlike chemical-based methods such as bisulfite or TAPS sequencing, which degrade DNA and diminish phasing and structural context, PacBio’s native detection maintains DNA integrity and supports haplotype-resolved analysis in complex genomic regions​. The licensing of HK2 marks another milestone in PacBio’s continued leadership in long-read epigenomics. Combined with the high accuracy and long read lengths of HiFi sequencing, HK2 delivers a uniquely powerful tool for understanding the full landscape of genome function—across both sequence and modification. "By enabling high-resolution, native detection of 5mC, 6mA, and 5hmC, we’re empowering researchers to ask more sophisticated questions and uncover new biology," said Mark Van Oene, Chief Operating Officer at PacBio. "And because this capability is powered entirely by software and existing sequencing signals, customers can access it with no added cost or workflow changes." PacBio aims to deliver these capabilities to Revio and Vega through a future software update. For more information about HiFi chemistry, visit https://www.pacb.com/technology/hifi-sequencing/. About Pacific BiosciencesPacBio (NASDAQ: PACB) is a premier life science technology company that designs, develops, and manufactures advanced sequencing solutions to help scientists and clinical researchers resolve genetically complex problems. Our products and technologies stem from two highly differentiated core technologies focused on accuracy, quality and completeness which include our HiFi long-read sequencing and our SBB® short-read sequencing technologies. Our products address solutions across a broad set of research applications including human germline sequencing, plant and animal sciences, infectious disease and microbiology, oncology, and other emerging applications. For more information, please visit www.pacb.com and follow @PacBio. PacBio products are provided for Research Use Only. Not for use in diagnostic procedures. About The Chinese University of Hong Kong (CUHK)Founded in 1963, CUHK is a leading comprehensive research university with a global reputation and world-leading rankings. Located in the heart of Asia, CUHK has a vision and a mission to combine tradition with modernity, and to bring together China and the West. The University is devoted in cutting edge research and translation of research outputs into useful products. CUHK is renowned for its leading role in molecular diagnostics research. The noninvasive prenatal diagnostic test for Down syndrome developed by Dennis Lo is widely adopted globally with more than 100 million tests performed since its inception. Centre for Novostics, an affiliate CUHK, is supported by the InnoHK initiative under the Innovation and Technology Commission of the Hong Kong Special Administrative Region Government dedicated to molecular diagnostic research. About Take2 Technology Limited (Take2)Founded in 2019, Take2 is a Hong Kong-based biotechnology company. Take2 focuses on the development of novel molecular diagnostic approaches, in particular in the area of epigenetic analysis and cancer screening. Forward Looking StatementsThis press release contains “forward-looking statements” within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and the U.S. Private Securities Litigation Reform Act of 1995. All statements other than statements of historical fact are forward-looking statements, including statements relating to the uses, advantages, quality or performance of, the benefits or expected benefits of using, PacBio products or technologies, including in connection with anticipated improvements to methylation detection with respect to 5hmC, 5mC, 6mA, and strand-specific 5mC, and related opportunities for customers to gain deeper insights, power new discoveries and enable clinical possibilities with no additional cost or change to sequencing protocols; setting new standards for accuracy, and other future events. You should not place undue reliance on forward-looking statements because they are subject to assumptions, risks, and uncertainties that could cause actual outcomes and results to differ materially from currently anticipated results. These risks include, but are not limited to, risks inherent in developing and commercializing new technologies; rapidly changing technologies and extensive competition in genomic sequencing; unanticipated increases in costs or expenses; interruptions or delays in the supply of components or materials for, or manufacturing of, PacBio products and products under development; third-party claims alleging infringement of patents and proprietary rights or seeking to invalidate PacBio's patents or proprietary rights; and other risks associated with general macroeconomic conditions and geopolitical instability. Additional factors that could materially affect actual results can be found in PacBio's most recent filings with the Securities and Exchange Commission, including PacBio's most recent reports on Forms 8-K, 10-K, and 10-Q, and include those listed under the caption “Risk Factors.” These forward-looking statements, including PacBio’s preliminary unaudited financial information and PacBio’s financial guidance, are based on current expectations and speak only as of the date hereof; except as required by law, PacBio disclaims any obligation to revise or update these forward-looking statements to reflect events or circumstances in the future, even if new information becomes available. Contacts Investors: Todd Friedmanir@pacificbiosciences.com Media:pr@pacificbiosciences.com

Marks the First-Ever Global Pediatric Trial for Menin Inhibitors The PedAL (Pediatric Acute Leukemia) Master Trial is at the heart of LLS's Dare to Dream Project to transform treatment and care for kids with blood cancer WASHINGTON, April 21, 2025 /PRNewswire/ -- The Leukemia & Lymphoma Society (LLS) announced today the first pediatric patient has received treatment in a new subtrial of its Pediatric Acute Leukemia (PedAL) Master Clinical Trial (NCT04726241). PedAL is a first-of-its-kind integrated worldwide master trial that tests multiple targeted drugs simultaneously to accelerate treatments for leukemia, the most common childhood cancer. Infants and children with specific types of relapsed/refractory leukemia (KMT2A-rearranged, NUP98-rearranged, or NPM1-mutant acute leukemia) are now eligible to enroll in the subtrial, which is investigating a combination of chemotherapy and a menin inhibitor. This subtrial involves pediatric patients with some of the most common and hardest-to-treat leukemias. In fact, 80% of infants with acute lymphoblastic leukemia have a genetic rearrangement of the KMT2A gene. About 40% of infants with acute myeloid leukemia have one of the three specific types of leukemia that the trial's treatment targets1. Menin inhibitors are a new and promising class of drugs that block the interaction between other proteins and the menin protein. Research has shown that the menin protein is responsible for driving progression of certain types of leukemia. The new subtrial is open in North America at Children's Hospital of Philadelphia, Cincinnati Children's Hospital, St. Jude Children's Research Hospital, Memorial Sloan Kettering Cancer Center, Lurie Children's Hospital of Chicago and SickKids - The Hospital for Sick Children in Toronto. Global trial sites are open in Spain, the Netherlands, France and Austria. "It is rare for a trial to be so ambitious and forward thinking about the needs of children while studies in adults are still ongoing. The new subtrial is evaluating the safety, efficacy and dosing for the treatment of certain acute leukemias in pediatric patients," says E. Anders Kolb, M.D. President and Chief Executive Officer of The Leukemia & Lymphoma Society. "Historically, cancer treatments have been evaluated in adults first and if successful, then children. This has resulted in a nearly decade-long delay between when therapies are first available for adults compared to children." The new subtrial brings LLS one step closer to achieving its bold goal: By 2040, LLS will enable patients with blood cancer to gain more than one million years of life. New trial expands on PedAL, builds on success of LLS's Dare to Dream Project PedAL launched in 2022 with one treatment subtrial investigating venetoclax. That trial is now open at approximately 80 clinical sites in 19 countries across the globe. Enrollment in the treatment trials begins with the robust PedAL screening trial (NCT04726241), open in 179 sites in the United States, Canada, Australia and New Zealand. To date, the screening trial has enrolled almost 450 children to identify their unique tumor biology and help match them to any targeted treatment clinical trial they are eligible for, whether in or outside of PedAL. Because blood cancers are more common in adults, there is a larger incentive for new treatments to be developed in that population, and progress for pediatric acute leukemia has fallen behind. PedAL is changing this paradigm. A delay in research and the development of therapies for children with aggressive forms of cancer threatens their survival. Today, leukemia is the second leading cause of cancer deaths in children. And for children who survive, 80% develop life-altering and chronic health issues from their treatment. "More children are being diagnosed with leukemia today than ever before," says Kim Schuetz, an oncology nurse, an LLS Dare to Dream Ambassador and mother to Austin, who was diagnosed with acute lymphoblastic leukemia in 2011. "We need to study more treatment options for these children. Through Dare to Dream, we're striving to transform care, so they don't experience a laundry list of life-long health issues and the possibility of developing secondary cancers because of treatment from standard therapies, such as harmful chemotherapies." LLS has supported the development of menin inhibitors over two decades In the early 2000s, LLS provided funding to a group of bright scientific investigators, which led them to discover the menin protein inside cancer cells and its role in the devastating effects of certain forms of leukemia. Over the next several years, LLS provided more than $6 million through its venture philanthropy program, the Therapy Acceleration Program (TAP), to scientists at the University of Michigan. They discovered small molecule inhibitors of the interaction of two proteins, menin and KMT2A/MLL, that, when fused together, drive progression of AML. With TAP funding, the scientists demonstrated the activity of their compounds in the laboratory setting. To facilitate translation of the scientists' progress in the laboratory to the clinic, LLS introduced the scientists to a clinical-stage biopharmaceutical company. Helping children with blood cancer survive and thrive Dare to Dream is transforming treatment and care for kids with blood cancer, so they not only survive but thrive after treatment. PedAL is an integral part of LLS's Dare to Dream Project along with support services, advocacy efforts and funding for blood cancer research: Research: With 35 active academic research grants totaling more than $31 million in funding commitments to pediatric and adolescent and young adult research, LLS-funded investigators are conducting groundbreaking research including exploring the origins of pediatric blood cancers and investigating increased incidence and better treatment options for leukemia in children with Down Syndrome. Advocacy: To ensure that more kids with blood cancer have better access to care, LLS advocates for meaningful changes at the state and federal level. A recent victory was the reauthorization of the Childhood Cancer Survivorship, Treatment, Access and Research (STAR) Act, which expanded childhood cancer research and created plans to enhance the tracking and reporting of pediatric cancer cases and treatment outcomes. Education & Support Services: LLS continues to expand its free patient education and personalized support services for pediatric patients and families to provide guidance, information and comfort during treatment and beyond. "The successes of the Dare to Dream Project, now and in the future, positions us well to reach our bold goal of enabling blood cancer patients to gain more than one million years of life by 2040," says Gwen Nichols, M.D., Chief Medical Officer of LLS. "Advances in treatment and care, spearheaded by Dare to Dream, will give even more children a chance to grow and thrive into adulthood." People can donate to LLS at any time. From May 12-16, all donations made to LLS will go directly to The Dare to Dream Project. Interested in donating to The Dare to Dream Project? Visit this link for more information. About The Leukemia & Lymphoma Society The Leukemia & Lymphoma Society® (LLS) is the global leader in the fight against blood cancer. The LLS mission: Cure blood cancer and improve the quality of life of all patients and their families. LLS funds lifesaving blood cancer research around the world, provides free information and support services, and is the voice for all blood cancer patients seeking access to quality, affordable, coordinated care. Founded in 1949, LLS has regions throughout the United States and Canada. To learn more, visit . Patients should contact the Information Resource Center at (800) 955-4572, Monday through Friday, 9 a.m. to 9 p.m. ET. For additional information, visit lls.org/lls-newsnetwork. Follow us on Facebook, X, Instagram, LinkedIn and TikTok. About The Dare to Dream Project Dare to Dream exists to transform treatment and care for kids with blood cancer. Because kids are different and need to be treated differently, Dare to Dream funds groundbreaking research and the LLS PedAL Master Clinical Trial as well as expands LLS support services and drives advocacy efforts to help all kids with blood cancers get accessible, affordable, quality healthcare. LLS proudly and gratefully acknowledges all those contributing to the LLS mission, including corporate partners Walgreens, Valvoline™ Global Operations, The Wawa Foundation, and Subaru of America, Inc. and its retailers who have each pledged over $1 million to Dare to Dream. LLS also recognizes Sarah Asma and the Moore family; The Don & Lorraine Freeberg Foundation; The Harry T. Mangurian Jr. Foundation; Norcross Foundation, Inc.; Joan and Paul Rubschlager; and The Bobby Zahurak Pediatric AML Research and Patient Support Fund for their outstanding contributions to Dare to Dream. For more information about Dare to Dream, including resources for patients and their families, trial details, and eligibility, visit: lls.org/dare-to-dream. About LLS PedAL As part of LLS's Dare to Dream Project, the Pediatric Acute Leukemia Master Trial (PedAL) is the first-of-its-kind global master clinical trial for pediatric acute leukemia patients that will fundamentally change how children are treated. Prior to enrolling in therapeutic trials, patients enroll in the PedAL Screening Trial (NCT04726241) to identify the unique tumor biology of each child's cancer and help them to match with the most promising treatment. The Screening Trial is currently open at multiple sites in the United States, Canada, Australia, and New Zealand. At this time, two PedAL therapeutic trials are open and actively enrolling patients in the U.S., Canada, Australia, New Zealand, Japan, and Europe, with more therapeutic trials planned for global execution. To learn more about PedAL, visit lls.org/dare-to-dream. PedAL would not be possible without the support of major foundation donors such as Gateway for Cancer Research, which pledged $1.5 million over three years to support genomic sequencing and flow cytometry, which is being conducted through the PedAL screening trial, and the Lisa Dean Moseley Foundation, which has committed $1.25 million over five years to support the PedAL Principal Investigators Fellowship Program, whose members are leading the PedAL screening trial and therapeutic trials. Media Contact: Sandra Salviejo Senior Director, Communications [email protected] Reference: 1 Juul-Dam KL et al. European Journal of Medical Genetics 2023 SOURCE The Leukemia & Lymphoma Society (LLS) WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

OTC2025论坛深度聚焦类器官与疾病建模、新药发现/研发、3D细胞培养、类器官培养及质控。展位咨询请联系：王晨 180 1628 8769。编者按：近日，在美国化学会（ACS）2025春季会议的“首次公开（First-time disclosures）”环节中，12款已进入或即将进入人体试验的小分子药物的化学结构首次公开亮相，这些潜在的新药覆盖了微生物感染、神经系统疾病、代谢疾病、心血管疾病等多个治疗领域。这些分子不仅在结构设计上展现出显著的创新性，其独特的作用机制也为相关疾病治疗开辟了新的路径。在这12款首次公开的创新药物当中，药明康德化学业务平台为其中5款提供赋能服务，助力前沿创新的快速转化。在今天的文章中，药明康德团队将依据ACS旗下C&EN网站的报道及公开信息，向读者介绍这些创新分子结构及其研发进展。候选药物：FG-2101研发机构：Blacksmith Medicines靶点：LpxC适应症：革兰氏阴性菌感染▲FG-2101的结构式（图片来源：参考资料[1]）LpxC是一种锌依赖性水解酶，特异性分布于革兰氏阴性菌中，而在革兰氏阳性菌及人类细胞中未见表达。这种独特的分布特征使LpxC成为理想的抗菌靶点——针对该酶开发的抑制剂可选择性杀灭革兰氏阴性病原菌，同时避免破坏肠道益生菌群。FG-2101作为一种新型LpxC抑制剂，展现出卓越的选择性（对其他细菌及人类金属酶的选择性>1万倍）和广谱抗菌活性，并在动物模型中显示出良好的静脉注射和口服活性。传统LpxC抑制剂普遍采用异羟肟酸基团与锌离子配位，但此类化合物在临床研究中均未取得突破，导致目前市场上尚无针对LpxC的有效药物。FG-2101通过创新性应用3-羟基-2-嘧啶酮作为金属结合基团，成功克服了异羟肟酸类LpxC抑制剂的毒性问题。该药物的研发采用无机化学驱动、基于片段的药物设计策略，现已完成了支持IND申请的临床前研究（IND-enabling），并有望在今年晚些时候进入临床试验阶段。候选药物：PRT3789研发机构：Prelude Therapeutics靶点：SMARCA2适应症：实体瘤▲PRT3789的结构式（图片来源：参考资料[1]）PRT3789是一种基于合成致死策略开发的SMARCA2蛋白降解剂，专门针对SMARCA4缺陷型肿瘤。在SMARCA4蛋白缺失或突变的癌症中，SMARCA2作为代偿性驱动因子促进肿瘤细胞生长。PRT3789通过选择性降解SMARCA2，实现对这类肿瘤的特异性抑制。SMARCA2蛋白降解剂的开发所面临的关键挑战是：SMARCA2与SMARCA4具有高度相似的溴结构域（介导蛋白相互作用的关键功能区），但SMARCA4在正常细胞中具有重要生理功能。PRT3789通过其分子结构中独特的手性甲基，精确调控降解剂的构象，使其能够选择性结合SMARCA2（而非SMARCA4）并与VHL E3连接酶形成三元复合物，从而通过泛素-蛋白酶体途径定向降解SMARCA2。临床前研究显示，PRT3789具有优异的选择性、理想的药代动力学（PK）特征和显著的体内抗肿瘤活性。目前，一项评估PRT3789联合Keytruda治疗SMARCA4突变的晚期、复发性/转移性实体瘤的2期临床试验正在进行中（NCT06682806）。候选药物：BMS-986458研发机构：百时美施贵宝（Bristol Myers Squibb）靶点：BCL6适应症：B细胞非霍奇金淋巴瘤▲BMS-986458的结构式（图片来源：参考资料[1]）BMS-986458是一种基于cereblon（CRBN）E3连接酶的蛋白降解剂，可选择性靶向BCL6蛋白，目前正在开发用于治疗B细胞非霍奇金淋巴瘤（B-NHL）。BCL6作为调控B细胞发育的关键转录调控因子，在多种B细胞恶性肿瘤中异常高表达。BMS-986458通过同时结合BCL6和CRBN，诱导BCL6的泛素化标记，进而通过蛋白酶体途径实现特异性降解。从分子结构来看，该药物含有三个立体中心，其中一个具有差向异构化倾向。临床前研究表明，该化合物能够快速且持续地降解BCL6，并对CRBN的常见新底物（neosubstrate）表现出高度选择性。在淋巴瘤动物模型中，BMS-986458显示出优异的体内抗肿瘤活性和良好的口服生物利用度。目前，BMS-986458已进入1期临床试验阶段（NCT06090539），评估其单药或联合标准疗法治疗复发/难治性B-NHL的安全性和初步疗效。候选药物：RP-1664研发机构：Repare Therapeutics靶点：PLK4适应症：实体瘤，儿童神经母细胞瘤▲RP-1664的结构式（图片来源：参考资料[1]）RP-1664是一种具有潜在"first-in-class"特性和口服生物利用度的PLK4选择性抑制剂，目前正在开发用于治疗TRIM37扩增型肿瘤。该化合物源于centrinone B的结构优化，通过系统的基于结构的设计和药代动力学特性改进，最终获得了这一具有显著药理学优势的候选药物。与centrinone B相比，RP-1664的关键结构差异在于用环丙基取代了甲氧基，这一修饰显著增强了分子的效力和选择性。临床前研究数据表明，RP-1664展现出良好的PK特性、激酶组选择性和显著的抗肿瘤活性，特别是在TRIM37扩增的动物肿瘤模型中。RP-1664目前已进入1期临床试验阶段（NCT06232408），用于评估其在晚期实体瘤患者中的安全性和初步疗效。候选药物：BMS-986238研发机构：百时美施贵宝靶点：PD-L1适应症：实体瘤▲BMS-986238的结构式（图片来源：参考资料[1]）BMS-986238是百时美施贵宝在BMS-986189的基础上开发的第二代大环肽类药物，通过结构优化成功克服了第一代药物半衰期短的局限性。该化合物通过选择性抑制免疫检查点蛋白PD-L1发挥抗肿瘤作用。为改善大环肽的PK特性，研发团队采用脂肪酸修饰策略，使分子能够与血清白蛋白可逆结合，从而显著延长体内循环时间，这一技术路线与已获批的GLP-1受体激动剂类减肥药物（如Wegovy和Zepbound）类似。在分子设计过程中，研究人员发现需要在脂肪酸与大环肽核心之间保持适当距离以维持最佳活性。通过引入聚乙二醇（PEG）连接链，成功实现了两个功能基团的空间隔离。最终获得的BMS-986238展现出优异的药物特性，包括：皮摩尔级别的PD-L1结合亲和力、长半衰期，以及理想的口服生物利用度。该药物可采用每周一次皮下注射或每日一次口服给药方案，为临床使用提供了灵活性。BMS-986238已于近期完成了1期临床试验（NCT06568458），为后续临床开发奠定了基础。候选药物：ALKS 2680研发机构：Alkermes靶点：OX2R适应症：发作性睡病、特发性嗜睡症▲ALKS 2680的结构式（图片来源：参考资料[1]）ALKS 2680是一种靶向食欲素2型受体（OX2R）的新型大环化合物，该受体在调节人体睡眠-觉醒周期中起关键作用。基于对OX2R配体结合特征的研究发现，传统小分子配体通常呈现C形构象。为此，研发团队创新性地设计了大环结构，通过共价连接子将这种关键的C形构象稳定锁定，从而优化了药物与受体的结合特性。目前，该候选药物正在多项临床试验中接受评估，其中包括一项针对1型发作性睡病患者的2期临床试验（NCT06358950），旨在评估其治疗这一睡眠障碍的疗效和安全性。候选药物：IAMA-6研发机构：Iama Therapeutics靶点：NKCC1适应症：神经系统疾病，包括自闭症谱系障碍、唐氏综合征和耐药性癫痫▲IAMA-6的结构式（图片来源：参考资料[1]）IAMA-6是一种新型选择性NKCC1抑制剂，正在开发用于治疗自闭症谱系障碍、唐氏综合征和耐药性癫痫等神经系统疾病。这些疾病的共同病理特征是与NKCC1介导的脑内氯离子稳态失衡。与早期NKCC抑制剂不同，IAMA-6通过独特的分子设计实现了对NKCC1的选择性，避免了同时抑制NKCC2（一种参与利尿作用的相关转运蛋白）所导致的副作用。该化合物的关键优势在于其良好的血脑屏障穿透能力，使其能够在中枢神经系统发挥治疗作用。IAMA-6能有效恢复脑内氯离子平衡，且不会引起利尿等不良反应。目前，IAMA-6已完成了1期临床试验（NCT06300398），Iama公司计划于2026年启动2期临床研究，进一步评估其治疗潜力。候选药物：ORIC-114研发机构：Oric Pharmaceuticals靶点：EGFR和HER2基因20号外显子插入突变适应症：携带EGFR或HER2基因20号外显子插入突变的非小细胞肺癌（NSCLC）▲ORIC-114的结构式（图片来源：参考资料[1]）携带EGFR或HER2基因20号外显子插入突变的非小细胞肺癌（NSCLC）患者，在疾病进展过程中常发生脑转移。然而，现有针对这类突变的靶向药物普遍存在血脑屏障穿透能力不足的局限性。ORIC-114是一种新型高选择性、不可逆的EGFR/HER2外显子20插入突变抑制剂，通过特异性与突变蛋白形成共价结合，展现出独特的治疗优势。临床前研究表明，ORIC-114不仅具有优异的血脑屏障穿透能力，还对中枢神经系统肿瘤（包括携带非典型EGFR突变的肿瘤）表现出显著抗肿瘤活性。在每日口服给药的NSCLC模型中，该药物可诱导肿瘤消退。ORIC-114目前正在开展1/2期临床试验（NCT05315700）以进一步评估其疗效和安全性。在1b期临床试验中，ORIC-114已展现出令人振奋的临床活性。其中一位晚期癌症女性患者的治疗经历尤为突出：在接受一轮ORIC-114治疗后，其四个脑部转移灶完全消失；经过两轮治疗后，肺部原发肿瘤也出现明显缓解。候选药物：AZD2389研发机构：阿斯利康（AstraZeneca）靶点：成纤维细胞激活蛋白（FAP）适应症：代谢功能障碍相关脂肪性肝炎（MASH）▲AZD2389的结构式（图片来源：参考资料[1]）MASH是一种以肝脏脂肪异常蓄积为特征的慢性肝病，可进展为肝纤维化，甚至肝硬化或肝癌，严重威胁患者生命。研究表明，FAP在肝纤维化进程中发挥关键作用，可能促进疾病恶化。AZD2389是一种新型FAP抑制剂，其分子结构中的腈基团可与FAP蛋白形成共价结合，从而高效抑制其活性。该药物的研发源于对噻唑烷类化合物的优化筛选，并借助人工智能技术加速了候选分子的发现与优化。临床前研究结果显示，在非人灵长类动物模型中，AZD2389可显著改善组织学纤维化程度，且耐受性良好。基于这些积极数据，AZD2389目前正在肝纤维化及代偿性肝硬化患者中进行2期临床试验（NCT06750276），以进一步评估其疗效与安全性。候选药物：PF-07853578研发机构：辉瑞（Pfizer）靶点：PNPLA3 I148M突变体适应症：代谢功能障碍相关性脂肪肝▲PF-07853578的结构式（图片来源：参考资料[1]）PNPLA3 I148M突变与肝脏脂肪堆积、炎症、纤维化及肝癌风险显著升高相关。研究表明，该突变会损害PNPLA3酶的正常功能，抑制肝脏脂质分解代谢，从而促进脂肪肝及相关肝病的进展。PF-07853578是一种靶向PNPLA3 I148M突变体的小分子共价抑制剂。其分子中的氨基甲酸酯基团可特异性结合PNPLA3 I148M的催化丝氨酸残基，形成共价键，促使突变蛋白从脂滴中清除，并进一步通过蛋白酶体途径降解致病蛋白。目前，PF-07853578已完成了1期临床试验（NCT05890105）。若后续开发进展顺利，该药物有望成为全球首个针对PNPLA3 I148M突变体的小分子疗法。候选药物：CK-4021586研发机构：Cytokinetics靶点：心肌纤维ATP酶适应症：射血分数保留型心力衰竭（HFpEF）▲CK-4021586的结构式（图片来源：参考资料[1]）CK-4021586是一种靶向心肌肌球蛋白ATP酶的创新小分子药物，该化合物的分子结构中含有一个独特的氮杂环丁烷甲醛基团，通过选择性地结合肌球蛋白的调节轻链，调节心脏收缩能力继而改善左心室舒张功能——这是HFpEF的核心病理生理特征，表现为心室舒张期主动松弛障碍。该药物目前正在进行1/2期临床试验（NCT06793371），旨在评估其在HFpEF患者中的安全性、药代动力学特征及初步疗效。候选药物：BAY 3389934研发机构：拜耳（Bayer）靶点：凝血因子IIa（FIIa）和凝血因子Xa（FXa）适应症：败血症引起的凝血功能障碍▲BAY 3389934的结构式（图片来源：参考资料[1]）败血症引发的凝血功能障碍是一种危及生命的并发症，这类患者往往临床预后不佳。BAY 3389934是一种静脉注射用短效FIIa/FXa双因子抑制剂，其分子设计采用代谢不稳定的酯结构，可实现快速清除。这一特性使得其在重症监护环境下能够精确调控抗凝强度，为败血症相关凝血病的治疗提供了更安全的干预手段。BAY 3389934目前已进入1期临床试验阶段（NCT06854640），以评估药物的安全性、确定最佳给药剂量，并初步探索其对败血症相关凝血病患者的治疗效果，为后续临床开发奠定基础。随着2025年美国化学学会春季会议的圆满落幕，这12款创新小分子药物的公开亮相，彰显了业界在多个治疗领域持续探索创新突破的努力。我们期待这些候选药物能够在后续研究中展现出良好的临床潜力，为患者带来更多治疗选择。参考资料：[1] 12 drug candidates debut in San Diego. 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