丙酮酸激酶

– FDA Accepted Agios’ Supplemental New Drug Application for PYRUKYND® (mitapivat) in Adult Patients with Non-Transfusion-Dependent and Transfusion-Dependent Alpha- or Beta-Thalassemia; PDUFA Goal Date is September 7, 2025 – – Topline Results from Phase 3 RISE UP Study of Mitapivat in Sickle Cell Disease to be Announced in Late 2025, with Potential U.S. Commercial Launch in 2026 – – Strong Financial Position Provides Opportunity to Maximize Potential PYRUKYND Commercial Launches, Advance Early- and Mid-Stage Clinical Programs and Expand Pipeline – CAMBRIDGE, Mass. , Jan. 13, 2025 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in cellular metabolism and pyruvate kinase (PK) activation pioneering therapies for rare diseases, today announced its anticipated key 2025 milestones and value-driving catalysts through 2026. The company’s management team will present this information at the 43rd Annual J.P. Morgan Healthcare Conference on Wednesday, January 15, 2025, at 7:30 a.m. PT / 10:30 a.m. ET . “2024 was marked by exceptional progress at Agios. We delivered on all our key priorities, advanced our potential best- and first-in-class rare disease pipeline and further strengthened our financial position. Today, we are entering an era of growth and expansion for the company, building on a strong foundation and focus, and are well-positioned for a sustained trajectory of success,” said Brian Goff, chief executive officer at Agios. “Our blueprint encompasses the potential for two additional commercial launches of PYRUKYND in thalassemia and sickle cell disease in 2025 and 2026, respectively, along with an early- and mid-stage pipeline that offers a strong foundation for innovation and growth, all supported by a highly experienced team with proven executional excellence and a strong balance sheet. Over the next 12 months, our priorities will be to maximize the potential of the PYRUKYND franchise, advance and diversify our key pipeline programs, and strategically focus our capital deployment to sustain our growth. We are excited about the future and the meaningful impact we can have in addressing the critical needs of rare disease patients.” 2024 Highlights: Thalassemia: Presented positive results from the ENERGIZE and ENERGIZE-T Phase 3 trials evaluating mitapivat versus placebo in adults with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia, respectively. The ENERGIZE randomized clinical trial results were presented at the European Hematology Association 2024 Hybrid Congress in June 2024 , and the ENERGIZE-T randomized clinical trial results were presented at the 66th American Society of Hematology Annual Meeting and Exposition in December 2024 . Agios filed regulatory applications for mitapivat (PYRUKYND) for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia with the U.S., European Union, Kingdom of Saudi Arabia and United Arab Emirates health authorities. Sickle Cell Disease: Completed enrollment of the Phase 3 RISE UP study that is evaluating mitapivat in sickle cell disease patients who are 16 years of age or older. This Phase 3 study enrolled more than 200 patients worldwide. Pediatric Pyruvate Kinase (PK) Deficiency: Reported topline results from the Phase 3 ACTIVATE-KidsT trial of mitapivat in children with PK deficiency who are regularly transfused. Further, completed enrollment of the Phase 3 ACTIVATE-Kids study of mitapivat in children with PK deficiency who are not regularly transfused. Lower-Risk Myelodysplastic Syndromes (LR-MDS): Initiated patient enrollment in the Phase 2b study of tebapivat (AG-946) in LR-MDS. Additionally, the U.S. Food and Drug Administration (FDA) granted orphan drug designation to tebapivat for the treatment of MDS. Early-Stage Pipeline: Dosed the first healthy volunteer participants in the Phase 1 study of AG-181, a PAH stabilizer, in phenylketonuria. Corporate Development: Announced a $905 million purchase agreement with Royalty Pharma for Agios’ rights to its vorasidenib royalty. Under the agreement, Agios received a payment of $905 million following the approval of vorasidenib by the FDA. Royalty Pharma will receive the entirety of the 15% royalty on annual U.S. net sales of vorasidenib up to $1 billion, and a 12% royalty on annual U.S. net sales greater than $1 billion. Agios retains a 3% royalty on annual U.S. net sales greater than $1 billion. Agios also received a $200 million milestone payment from Servier following the FDA approval of vorasidenib. Altogether, Agios received a total of $1.1 billion in milestone payments as part of this purchase agreement. Entered into a distribution agreement with NewBridge Pharmaceuticals to advance commercialization of PYRUKYND in the Gulf Cooperation Council (GCC) region. NewBridge, a leading specialty company headquartered in Dubai, will commercialize PYRUKYND in Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates. Announced a $905 million purchase agreement with Royalty Pharma for Agios’ rights to its vorasidenib royalty. Under the agreement, Agios received a payment of $905 million following the approval of vorasidenib by the FDA. Royalty Pharma will receive the entirety of the 15% royalty on annual U.S. net sales of vorasidenib up to $1 billion, and a 12% royalty on annual U.S. net sales greater than $1 billion. Agios retains a 3% royalty on annual U.S. net sales greater than $1 billion. Agios also received a $200 million milestone payment from Servier following the FDA approval of vorasidenib. Altogether, Agios received a total of $1.1 billion in milestone payments as part of this purchase agreement. Entered into a distribution agreement with NewBridge Pharmaceuticals to advance commercialization of PYRUKYND in the Gulf Cooperation Council (GCC) region. NewBridge, a leading specialty company headquartered in Dubai, will commercialize PYRUKYND in Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates. Anticipated 2025 Milestones: Thalassemia: Receive FDA regulatory decision for PYRUKYND for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia. The review classification for the company’s supplemental New Drug Application is Standard and the Prescription Drug User Fee Act (PDUFA) goal date is September 7, 2025. Sickle Cell Disease: Announce topline results from the Phase 3 RISE UP study of mitapivat in sickle cell disease in late 2025, with a potential U.S. commercial launch in 2026. Additionally, begin patient enrollment for the Phase 2 study of tebapivat in sickle cell disease in mid-2025. Pediatric Pyruvate Kinase (PK) Deficiency: Announce topline results from the Phase 3 ACTIVATE-Kids study of mitapivat in children with PK deficiency who are not regularly transfused in early 2025. Lower-Risk Myelodysplastic Syndromes (LR-MDS): Complete patient enrollment in the Phase 2b study of tebapivat for LR-MDS in late 2025. Early-Stage Pipeline: File an Investigational New Drug Application for AG-236, a siRNA targeting TMPRSS6 intended for the treatment of polycythemia vera, in mid-2025. Presentation at 43rd Annual J.P. Morgan Healthcare Conference Agios’ management team will present at the 43rd Annual J.P. Morgan Healthcare Conference on Wednesday, January 15, 2025 , at 7:30 a.m. PT / 10:30 a.m. ET . The live webcast will be accessible on the Investors section of the company's website (www.agios.com) under the “Events & Presentations” tab. A replay of the webcast will be archived on the company’s website for at least two weeks following the presentation. About PYRUKYND® (mitapivat) U.S. INDICATIONPYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. U.S. IMPORTANT SAFETY INFORMATIONAcute Hemolysis: Acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible. When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath. Hepatocellular Injury in Another Condition: In patients with another condition treated with PYRUKYND at a higher dose than that recommended for patients with PK deficiency, liver injury has been observed. These events were characterized by a time to onset within the first 6 months of treatment with peak elevations of alanine aminotransferase of >5× upper limit of normal (ULN) with or without jaundice. All patients discontinued treatment with PYRUKYND, and these events improved upon treatment discontinuation. Obtain liver tests prior to the initiation of PYRUKYND and monthly thereafter for the first 6 months and as clinically indicated. Interrupt PYRUKYND if clinically significant increases in liver tests are observed or alanine aminotransferase is >5x ULN. Discontinue PYRUKYND if hepatic injury due to PYRUKYND is suspected. Adverse Reactions: The most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia. Drug Interactions: Strong CYP3A Inhibitors and Inducers: Avoid concomitant use. Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily. Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage. Sensitive CYP3A, CYP2B6, CYP2C Substrates Including Hormonal Contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index. UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment. Please see full Prescribing Information for PYRUKYND. About AgiosAgios is the pioneering leader in PK activation and is dedicated to developing and delivering transformative therapies for patients living with rare diseases. In the U.S. , Agios markets a first-in-class pyruvate kinase (PK) activator for adults with PK deficiency, the first disease-modifying therapy for this rare, lifelong, debilitating hemolytic anemia. Building on the company's deep scientific expertise in classical hematology and leadership in the field of cellular metabolism and rare hematologic diseases, Agios is advancing a robust clinical pipeline of investigational medicines with programs in alpha- and beta-thalassemia, sickle cell disease, pediatric PK deficiency, myelodysplastic syndrome (MDS)-associated anemia and phenylketonuria (PKU). In addition to its clinical pipeline, Agios is advancing a preclinical TMPRSS6 siRNA as a potential treatment for polycythemia vera. For more information, please visit the company’s website at www.agios.com. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the potential benefits of PYRUKYND® (mitapivat), tebapivat (AG-946) , AG -236 and AG-181, Agios’ PAH stabilizer; Agios’ plans, strategies and expectations for its preclinical, clinical and commercial advancement of its drug development, including PYRUKYND®, tebapivat, AG-181 and AG-236; the submission of PYRUKYND® to regulators for approval in alpha-and-beta thalassemia; Agios’ strategic vision and goals, including its key milestones for 2025; and the potential benefits of Agios’ strategic plans and focus. The words “anticipate”, “expect”, “goal”, “hope”, “milestone”, “opportunity”, “plan”, “potential”, “possible”, “strategy”, “will”, “vision”, and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios’ current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios’ product candidates will successfully continue. There can be no guarantee that any positive developments in Agios’ business will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other important factors, including, without limitation: risks and uncertainties related to the impact of pandemics or other public health emergencies to Agios’ business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products; Agios’ results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. FDA, the EMA or other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Agios’ ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials; unplanned cash requirements and expenditures; competitive factors; Agios' ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing; Agios’ ability to establish and maintain key collaborations; uncertainty regarding any royalty payments related to the sale of its oncology business or any milestone or royalty payments related to its in-licensing of AG-236, and the uncertainty of the timing of any such payments; uncertainty of the results and effectiveness of the use of Agios’ cash and cash equivalents; and general economic and market conditions. These and other risks are described in greater detail under the caption "Risk Factors" included in Agios’ public filings with the Securities and Exchange Commission . Any forward-looking statements contained in this press release speak only as of the date hereof, and Agios expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. Contacts: Investor Contact Chris Taylor , VP, Investor Relations and Corporate Communications Agios Pharmaceuticals IR@agios.com Media Contact Eamonn Nolan , Senior Director, Corporate Communications Agios Pharmaceuticals Media@agios.com Source: Agios Pharmaceuticals, Inc.

“ 点击蓝字 关注我们 周璐 复旦大学药学院教授，副院长，教育部青年长江学者（2019），中国药学会药物化学专委会委员。主要针对潜在糖脂代谢药靶开发全新小分子调节剂，用于抗肿瘤及抗炎治疗。作为通信（含共同）作者在国际一流期刊包括 Cell Metab, Nat Struc Mol Biol, PNAS, JACS 发表论文 30 余篇，获授权国内外专利 10项，国际专利 3 项，2 项新药研发项目已完成成果转化，获得中国药学会科学技术二等奖（第一完成人）。 靶向肿瘤代谢酶小分子药物研究进展 PPS  李顺尧，冯磊，张昕晨，黄逸洋，姚雪莹，周璐 * （复旦大学药学院，上海 201203） [ 摘要 ] 肿瘤细胞通过代谢重编程适应快速生长和分裂的需求，表现出与正常细胞不同的代谢特征，包括葡萄糖和氨基酸摄取失调、利用中心碳代谢支持生物合成、对氧化应激保护机制的依赖增加等。这些特征为靶向肿瘤代谢提供了潜在的治疗策略。综述糖、氨基酸、脂质及核酸代谢通路中的关键代谢酶及其靶向药物的研究进展，并展望了未来药物研发的新方向，以期为肿瘤治疗提供参考。 糖、氨基酸、脂质及核酸是细胞的基本组成部分，其正常代谢对细胞生命活动至关重要 [1]。肿瘤细胞快速生长和分裂需要大量的营养物质和能量，通过代谢重编程，肿瘤细胞可以调整相应的转运体和代谢酶 [2-3]，以适应肿瘤微环境，展现出与正常细胞不同的代谢表型和异质性 [4]。 肿瘤代谢的主要特征有以下几条：1）葡萄糖和氨基酸摄取失调 [5]；2）利用中心碳代谢支持生物合成 [6]；3）采用机会性营养获取模式获取能量；4）对电子受体的需求扩大；5）对氧化应激保护机制的依赖增加 [7]；6）对“氮”的需求增加；7）不同肿瘤代谢适应具有异质性 [8]；8）代谢驱动信号通路改变；9）代谢与肿瘤微环境之间存在相互作用；10）融入全身代谢系统。 这些肿瘤代谢特征促进肿瘤的发生发展，保证肿瘤在不同环境下的生长代谢。同时，这些特异性代谢机制为靶向肿瘤代谢进行治疗提供了可能性。本文将简述糖、氨基酸、脂质及核酸的肿瘤代谢通路（见图 1），重点介绍部分代谢酶的临床小分子药物研究进展，并展望靶向肿瘤代谢药物发展的新方向，以期为药物研发提供参考，推动肿瘤治疗的新进展。 1 靶向肿瘤糖代谢 1.1 糖酵解通路及相应临床在研药物 尽管肿瘤代谢研究始于 Warburg 效应，但目前靶向糖酵解的抗肿瘤药物大多处于临床前研究阶段，只有少数药物进入临床试验（见表 1）。 1.1.1 靶向 6-磷酸果糖-2-激酶/果糖-2，6-双磷酸酶 3 临床在研药物 磷酸果糖激酶 1（phospho-fructokinase-1，PFK-1）能够催化 6-磷酸果糖磷酸化生成 1，6-二磷酸果糖（fructose 1，6-bisphosphate，FBP），是糖酵解中 3 个不可逆反应之一，也是限速步骤。6-磷酸果糖-2-激酶/果糖-2，6-双磷酸酶 3（6-phosphofructo-2-kinase/fructose-2，6-biphosphatase 3，PFKFB3）能够催化 6- 磷酸果糖磷酸化生成 2，6-二磷酸果糖（见图 1），变构激活 PFK-1，对糖酵解途径的调控有较大影响。PFKFB3 蛋白在多种癌症中过表达，其高表达和高活性与癌症的侵袭性和不良预后密切相关。研究发现，抑制 PFKFB3 会导致细胞凋亡、细胞周期停滞、自噬、DNA 损伤、巨噬及化疗增敏 [9]，因此开发 PFKFB3 靶向抑制剂是潜在的肿瘤治疗策略。 PFK-158[10] 是目前唯一靶向 PFKFB3 的临床在研药物，对 PFKFB3 有较好抑制作用（IC50 = 137 nmol· L-1），也是首个临床在研的靶向抑制糖酵解药物 [11]，目前处于Ⅱ期临床。PFK-158 对 Th17 细胞和髓源性抑制细胞（myeloid-derived suppressor cell，MDSC）具有免疫调节作用。实验结果表明，PFK-158 能在体内降低晚期癌症患者外周血中的Th17 细胞、γδT17 细胞和 MDSC，增加活化的效应CD4+ 和 CD8+ T 细胞。这意味着 PFK-158 与靶向药物及免疫治疗药物联合用药可能带来额外的临床益处 [12]。目前，PFK-158 的Ⅱ期临床试验仍在进行中，预计于 2025 年完成，主要研究 PFK-158 与奥比努图珠单抗等药物联用对复发或治疗无效的Ⅰ-Ⅲa 级滤泡性淋巴瘤的治疗效果。 1.1.2 靶向丙酮酸激酶 M2 临床在研药物 丙酮酸激酶（pyruvate kinase，PK）是另一种关键的糖酵解酶，是糖酵解途径中最后的限速酶，能够不可逆地将磷酸烯醇丙酮酸（phosphoenolpyruvate，PEP）和腺苷二磷酸（adenosine diphosphate，ADP）催化生成丙酮酸和腺苷三磷酸（adenosine triphosphate，ATP）。PK 在肌肉组织中具有 PKM1 和 PKM2 亚型，二者之间的显著区别在于其催化活性，PKM1 能够自发形成高活性的四聚体，PKM2 则会形成催化效率较低的二聚体 [13]。PKM1 主要存在于终末分化的细胞中，与肿瘤的发生发展关系较小 [13]，PKM2则主要存在于增殖细胞及大部分肿瘤细胞，能被FBP 变构激活（AC50 = 7.0 μmol· L-1）[14]。肿瘤细胞中 PKM2 的低活性，使得糖酵解中的上游中间体累积，进而激活其他生物合成途径，如脂质和核苷酸的合成 [15]，促进肿瘤的发生发展。目前临床上靶向PKM2 的分子包括 2 个激动剂和 1 个已终止的抑制剂（见表 1）。 TP-1454 是首个进入临床研究的 PKM2 小分子激动剂。TP-1454 通过 in-house 的片段筛选并经过改造得到（见图 2）[16]。起初的苗头分子 1 对PKM2 有一定激动活性（AC50 = 36 μmol· L-1）且最大激动效果与 FBP 相当。随后对酰胺氮原子处的化学孔间进行探索合成得到了化合物 2，在此基础上进一步改造发现了活性更优的先导化合物 3，其对PKM2 有更好的激活效果（AC50=0.011 μmol·L-1），且在肺癌细胞 A549 及 H1299 上展现出一定的抑制活性。在进一步改造后，得到了临床候选分子 TP-1454[17-18]。药效学研究显示 [19]，TP-1454 在与程序性死亡受体 1（programmed cell death protein 1，PD-1）和细胞毒性 T 淋巴细胞相关蛋白 4 （cytotoxic T-lymphocyte-associated protein 4，CTLA-4）抗体联用时能显著增强抗肿瘤效果，并且对小鼠体重无显著影响，证实了该分子的有效性和安全性。目前 TP-1454 处于Ⅰ期临床，用于治疗转移性及晚期实体瘤 [20]，预计于 2025 年 12 月完成Ⅰ期临床研究。 ACT-001 是 PKM2 的选择性激动剂 [21]，能在生理条件下缓慢释放出乌心石内酯（micheliolide，MCL）[22]。ACT-001 及原型药 MCL 对 HL-60/A 细胞均有一定抑制效果 [IC50 分别为（21.5±2）和（6.2±2.2）μmol· L-1]；ACT-001 在急性髓细胞性白血病（acute myelogenous leukemia，AML）NOD/SCID 小鼠模型上展现出较好药效，将模型鼠平均生存时长延长至 63 天（空白对照组为 43 天），并能够显著抑制骨髓中 CD45+ CD33+ 肿瘤细胞（抑制率达 98.4%）；同时，小鼠急毒实验显示 ACT-001 对肝、心及肾脏无明显毒性 [22]。后续研究发现 ACT-001 及 MCL 对胶质瘤等其他恶性肿瘤也有一定抑制效果 [23]。ACT-001 作为天然产物衍生物，具有多个潜在靶点与复杂的抗肿瘤机制。近年来研究发现，PKM2 是 ACT-001 的原型药 MCL 的作用靶点之一。MCL 能够高选择性地对 PKM2 的 424 位半胱氨酸进行共价结合，促进 PKM2 活性四聚体的形成 [21, 24]，对 PKM2 有非常好的激活效果（AC50 = 6 nmol·L-1），同时 MCL 的抗肿瘤活性依赖于 PKM2 的表达 [21]。ACT-001 目前正在美国进行Ⅰ/Ⅱ期临床试验用于多种实体瘤治疗，结果显示其耐受性良好，未发现明显毒性 [25]。 1.2 三羧酸循环通路及相应临床在研药物 肿瘤细胞利用三羧酸循环（tricarboxylic acid cycle，TAC）中间体进行生物合成，因此，靶向TAC 中的关键代谢产物是肿瘤治疗的潜在策略。表2 列举了靶向 TAC 代表性临床在研药物。 1.2.1 靶向丙酮酸脱氢酶及丙酮酸脱氢酶激酶临床在研药物 丙酮酸脱氢酶复合体（pyruvate dehydrogenase complex，PDC）通过催化丙酮酸不可逆脱羧为乙酰辅酶 A，是代谢中的关键酶，靶向调控 PDC具 有 重 要 意 义。 丙 酮 酸 脱 氢 酶 激 酶（pyruvate dehydrogenase kinase，PDK）能够对 PDC 进行磷酸化，降低其活性。肿瘤细胞通过上调 PDK 的表达水平，减少 PDC 活性，从而更倾向于进行糖酵解 [26]。 二氯乙酸盐（sodium dichloroacetate，DCA）是一种通过恢复 PDC 活性发挥抗肿瘤效果的小分子，它通过抑制 PDK 活性，恢复 PDC 的活性改变肿瘤酸性微环境 [27]，并能逆转由于 PDK4 导致的肿瘤耐药问题 [28]。DCA 与多种抗肿瘤药物联用，如紫杉醇、阿霉素及沙利霉素，在体内外实验中显示了一定的效果，并且没有严重血液学、肝、肾或心脏毒性 [28]。在针对局部晚期头颈部鳞状细胞癌的 DCA 联合同步放化疗的Ⅱ期临床试验中，DCA 添加组与安慰剂组相比有着更高的完全反应率（71.4% vs 37.5%，p = 0.036 2），并且在治疗后能够显著降低丙酮酸和乳酸的含量（治疗组与基线组含量之比分别为 0.47 和0.61，p ＜ 0.005）[29]。 CPI-613 是硫辛酸类似物，通过干扰硫辛酸作为氧化还原辅因子的功能抑制 PDC 和 α-酮戊二酸脱氢酶复合体（α-ketoglutarate dehydrogenase complex，α-KGDH）的活性 [27]。CPI-613 对 α-KGDH 的抑制是通过调节 E3 亚基产生的活性氧实现；对 PDC 的抑制则是通过调节 PDK 的活性间接影响 PDC 活性 [30]。目前临床结果显示，CPI-613 与常规化疗药物联用后效果显著优于单用药物 [31]，如 CPI-613 与大剂量阿糖胞苷和米托蒽醌联合应用的疗效显著，老年患者的完全缓解率为 52%，中位生存期为 12.4 个月 [32]，显示出 CPI-613 的成药潜力。在Ⅰb 期临床试验中，未观察到 4 级毒性，经过中位 15.6 个月的随访，客观缓解率为 45%，中位无进展生存期为 10 个月（95%置信区间，7.1~14.9）[33]。 1.2.2 靶向异柠檬酸脱氢酶临床在研药物 异柠檬酸脱氢酶（isocitrate dehydrogenase，IDH） 在TAC 中催化异柠檬酸氧化脱羧形成 α-酮戊二酸（α-ketoglutarate，α-KG）和 CO2，并将烟酰胺腺嘌呤二核苷酸磷酸（nicotinamide adenine dinucleotide phosphate，NADP+）还原为还原型烟酰胺腺嘌呤 二 核 苷 酸 磷 酸（reduced nicotinamide adenine dinucleotide phosphate，NADPH），其活性与脂质和固醇的生物合成密切相关，也与氧化还原平衡的调节有关。IDH1/2 在多种肿瘤中均有发现相应的突变，突变型异柠檬酸脱氢酶（mutant isocitrate dehydrogenase，mIDH）能够将 α-KG 转化为 D-2-羟基戊二酸（D-2-hydroxyglutarate，D-2HG），并将NADPH 转化为 NADP+，导致基因表达失调、DNA损伤修复障碍和炎症。同时，D-2HG 与 α-KG 结构相似，能竞争性抑制 α-KG 依赖的双加氧酶，导致表观修饰失调，形成过度甲基化的表型 [34]。 目前已有 3 个 IDH 抑 制 剂 上 市， 分 别 是enasidenib，olutasidenib 及 ivosidenib， 这 3 款药物的临床适应证均为急性髓细胞样白血病 [35]。在实体瘤治疗方面，IDH 抑制剂仍有所欠缺，ivosidenib和 enasidenib 在脑中的暴露量较少，难以用于治疗IDH 突变的胶质瘤。Vorasidenib（AG-881）是首款针对 mIDH1/mIDH2 的双重抑制剂，对 IDH1-R132H及 IDH2-R140Q 突变体有着非常好的抑制效果（mIDH1-IC50=6 nmol·L-1，mIDH2-IC50=12 nmol·L-1），且透脑性较好，能够显著降低脑内 D-2HG 的含量。在临床上，接受 vorasidenib 治疗的患者，其肿瘤组织中 mIDH 的代谢产物 D-2HG 浓度平均降低了90% 以上 [36]，并在Ⅲ期临床试验中展现出较好的疗效：与安慰剂组相比，vorasidenib 组 2 级 IDH 突变型胶质瘤患者的中位无进展生存期显著延长（27.7个月 vs 11.1 个月），疾病进展或死亡的风险比为0.39[37]。 1.3 靶向糖代谢在调控肿瘤免疫微环境中的应用前景 葡萄糖对于 T 细胞的增殖及功能十分重要，由于肿瘤细胞对于环境中葡萄糖大量摄取，造成周遭环境极度缺乏营养，因此对肿瘤周围的免疫细胞有较大影响。一方面，肿瘤浸润淋巴细胞为了满足自身营养物质需求，会促进氧化磷酸化过程造成活性氧产生，最终导致肿瘤浸润免疫细胞的失调及耗竭[38]。另一方面，在缺乏葡萄糖环境中，肿瘤相关巨噬细胞更倾向朝促进肿瘤的 M2 样表型转变，并能够促进多种肿瘤细胞的生长 [8]。 此外，由于 Warburg 效应的存在，肿瘤微环境中的乳酸大量蓄积从而使 CD8+ T 细胞、自然杀伤细胞及树突状细胞的活性降低，并使肿瘤相关巨噬细胞极化为耐受性 M2 样表型 [39]。调节性 T 细胞也会通过 MCT1 摄取乳酸并上调 PD-1 表达，从而促进肿瘤免疫逃逸 [40]。其他一系列代谢产物如富马酸、琥珀酸、衣康酸及 D-2HG 等除了本身的代谢功能，也在肿瘤微环境中发挥着重要作用 [41]。 因此对开发靶向代谢酶的小分子调节剂而言，干扰肿瘤微环境，进而消除耗竭免疫细胞，是潜在的治疗策略。尽管目前靶向肿瘤微环境代谢的证据主要来自临床前研究，但这些策略具有较好的临床应用前景，值得进一步探索。 2 靶向肿瘤氨基酸代谢 2.1 靶向谷氨酰胺代谢 谷氨酰胺是癌细胞生长和增殖的第二大营养来源，为生物合成途径提供碳源。大多数癌细胞在代谢重编程后对谷氨酰胺表现出高度依赖性，这也被称为“谷氨酰胺成瘾”[42]。谷氨酰胺代谢通路中涉及的谷氨酰胺转运体、谷氨酰胺酶（glutaminase，GLS）、转氨酶等，对癌细胞生存至关重要 [43]，靶向这些与谷氨酰胺代谢相关的蛋白，在癌症治疗中表现出巨大的潜力，促进了新的抗癌候选药物的开发。 GLS 是多种肿瘤中生长和增殖的关键酶 [44]，能够将谷氨酰胺转化为谷氨酸。表 3 列举了目前正处于临床研究的 GLS 小分子抑制剂。 L-DON 是一类谷氨酸类似物，对 GLS 产生不可逆的抑制 [44-45]。在临床研究中，L-DON 表现出抗霍奇金淋巴瘤和抗胶质母细胞瘤活性 [44]。DRP-104（sirpiglenastat）是 L-DON 的前药，胃肠道不良反应小，在进入肿瘤组织后能够活化释放出原药L-DON[46]，在临床试验中与 PD-L1 抗体药物联合使用，用于晚期实体瘤治疗。 CB-839 是另一个处于临床阶段的 GLS1 小分子抑制剂（GLS1: IC50= 31 nmol·L-1；GLS2: IC50 ＞50 000 nmol·L-1），主要与其他抗癌药物联合使用。目前，该药通常与阿扎胞苷联合治疗骨髓增生异常综合征，与 sapanisertib 联合治疗非小细胞肺癌，与nivolumab 联合治疗黑色素瘤、透明细胞肾细胞癌和非小细胞肺癌，于放疗后与替莫唑胺联合治疗 IDH介导的弥漫性星形细胞瘤。在近期Ⅰb/Ⅱ期临床试验结果中显示 [47]，针对晚期骨髓增生异常综合征患者，CB-839 与阿扎胞苷联用具有良好的耐受性，客观缓解率为 70%，其中 53% 的参与者达到（骨髓）完全缓解，中位总生存期为 11.6 个月。 IPN-60090 是 CB-839 的结构类似物，但化合物IPN-60090具有更优的理化性质和药代动力学特征，在联合哺乳动物雷帕霉素靶蛋白复合体 1/2 双重抑制剂用于非小细胞肺癌的治疗中，表现出良好的药效 [48]。 2.2 靶向精氨酸代谢 精氨酸（arginine）直接或间接参与许多生物过程，包括细胞增殖、细胞信号转导、肌肉收缩、免疫、神经传递、血管舒张、生长因子和其他氨基酸的合成 [49]。许多癌细胞对外部精氨酸高度依赖，通过抑制精氨酸代谢酶如精氨酸酶（arginase，ARG）、精氨酸脱羧酶（arginine decarboxylase，ADC）和精氨酸脱亚胺酶（arginine deiminase，ADI），以此靶向外源性精氨酸已成为治疗多种癌症的重要手段 [50-51]。 ARG1 是调节精氨酸代谢的重要靶点之一。CB-1158（见表 4）为口服有效的选择性 ARG1 小分子抑 制 剂（Arg1: IC50 = 86 nmol· L-1；Arg2: IC50 = 296 nmol· L-1），通过阻断精氨酸耗竭来逆转对 T 细胞增殖的抑制，从而杀伤肿瘤细胞 [52]，目前 CB-1158处于Ⅰ/Ⅱ期临床阶段，采用单用或与 PD-1 单抗联合使用的给药方式，用于结直肠癌、非小细胞肺癌和黑色素瘤的治疗。 2.3 靶向甲硫氨酸代谢 甲硫氨酸（methionine，Met）为含硫必需氨基酸，主要是通过外部获得。它是琥珀酰辅酶 A、同型半胱氨酸、半胱氨酸、肌酸和肉毒素等的前体，参与细胞内 S-腺苷甲硫氨酸（S-adenosyl-methionine，SAM）、多胺、肌酸和磷脂酰胆碱的生物合成。肿瘤细胞缺乏内源性 Met 生物合成，表现出对外源性Met 的严重依赖性，即霍夫曼效应 [53]。针对肿瘤中Met代谢的药物，如甲硫氨酸腺苷转移酶（methionine adenosyltransferase，MAT）抑制剂，已被证明具有治疗肿瘤的潜力 [54]。 MAT2A 的功能是催化 ATP 和 Met 生 成SAM，而后者是核酸、磷脂、组蛋白、生物胺和蛋白质甲基化的甲基供体。MAT2A 在多种肿瘤中都异常表达；抑制 MAT2A 可抑制癌细胞生长、增殖和迁移，MAT2A 作为癌症治疗靶点也受到广泛关注 [55]。 AG-270 是由 Agios 公司通过高通量筛选及虚拟筛选，并通过基于结构的药物设计开发所得（见表 5）[56]，有较好的体外活性，吸收、分布、代谢和排泄性质以及口服生物利用度。AG-270 于 2023年 4 月完成了Ⅰ期临床试验，研究了 AG-270 单用或与紫杉醇以及吉西他滨联用在甲硫腺苷磷酸化酶（methylthioadenosine phosphorylase，MTAP）基因缺失的晚期实体瘤或淋巴瘤患者中的安全性、药代动力学及临床药效，但该药物目前因安全性及疗效问题已终止临床研究。IDE-397 是 IDEAYA 公司发现的另一款口服有效的 MAT2A 抑制剂，已在美国进入Ⅰ期临床试验，单用或与紫杉烷类抗癌药物（多西他赛、紫杉醇）、戈沙妥珠单抗联用以评估其在转移性癌症患者中的安全性、有效性、药效学和抗肿瘤活性（见表 5）。此外，IDE-397 与蛋白质精氨酸酶甲基转移酶 5 小分子抑制剂 AMG-193 联合疗法也正处于Ⅰ/Ⅱ期临床。 2.4 靶向色氨酸代谢 色氨酸为必需氨基酸，超过 95% 的色氨酸通过色氨酸降解参与犬尿氨酸（kynurenine，Kyn）合成过程。通过这一途径，产生一些与免疫反应和神经传递相关的生物活性代谢物。色氨酸代谢主要发生在肝脏，经犬尿氨酸途径生成各种犬尿氨酸代谢物，其中限速酶为吲哚胺 2，3-双加氧酶 1/2（indoleamine 2，3-dioxygenase 1/2，IDO1/2）和色氨酸 2，3-双加氧酶（tryptophan-2，3-dioxygenase，TDO）。研究表明，大多数人类肿瘤组织中高表达IDO[57]，且 IDO/TDO 活性与癌症免疫逃逸机制以及T 细胞活性的调节密切相关 [58]，靶向 IDO/ TDO 小分子抑制剂的开发成为靶向抗癌药物研发策略之一。表6 列举了目前正处于临床研究的 IDO1 小分子抑制剂。 目前，indoximod，navoximod，epacadostat，linro-dostat 和 PF-0680003 是进入临床阶段的 IDO1 小分子抑制剂（见表 6）。色氨酸类似物 indoximod （NLG-8189）是 NewLink 公司开发的首个临床候选药物，于 2017 年启动与免疫检查点抑制剂联合治疗黑色素瘤的Ⅲ期临床试验。同时，indoximod 的前药形式NLG-802于2017年也进入Ⅰ期临床试验[59-60]。然 而，indoximod（hIDO1: IC50 ＞ 100 mmol· L-1，HeLa IDO1: IC50 ＞ 2.5 mmol· L-1）及其前药并非特异性的 IDO1 抑制剂，其作用机制仍存在争议 [61]。近年来，还有许多不同类型母核结构的 IDO1 小分子抑制剂被陆续报道，也有许多小分子是 IDO1，IDO2 和 TDO 的泛抑制剂，IDO1 小分子抑制剂与组蛋白脱乙酰酶抑制剂、DNA 烷基化试剂、tubulin抑制剂以及 E3 配体偶联形成双功能分子也被开发并得到了广泛应用 [62]。 然而，目前大部分 IDO1 抑制剂的临床研究均已终止，失败的原因主要如下： 1）靶点的局限性。IDO1 抑制剂主要通过抑制IDO1 来阻止肿瘤细胞的免疫逃逸，但肿瘤微环境中涉及的免疫抑制机制非常复杂，单靠抑制 IDO1 不足以产生显著的抗肿瘤效果 [63]。 2）肿瘤微环境的复杂性。肿瘤微环境中存在 多 种 免 疫 抑 制 因 子， 如 TDO，PD-1/PD-L1 和CTLA-4 等，肿瘤细胞能绕过 IDO 途径，从而产生耐药 [63-64]。 3）非依赖 IDO1 的代谢途径。白细胞介素 4 诱导蛋白 1（interleukin 4 induced protein 1，IL4I1）通过独立于 IDO1 的机制继续促进肿瘤免疫逃逸，IL4I1 为分泌型 L-氨基酸氧化酶，主要通过代谢产生犬尿喹啉酸和其他内源性代谢物，激活芳香烃受体，从而在肿瘤微环境中发挥免疫抑制作用，这可能也是 IDO1 抑制剂在某些情况下疗效不佳的原因之一 [65]。 4）IDO 抑制剂本身缺陷。IDO 抑制剂在药代动力学特性上存在不足，如生物利用度低或代谢过快，或者在长期使用中出现不可接受的毒性反应，影响其临床应用 [63]。 2.5 靶向氨基酸代谢在调控肿瘤免疫微环境中的应用前景 氨基酸代谢除了在维持肿瘤生长中发挥重要作用外，在肿瘤免疫微环境的调节中也具有重要意义。首先，肿瘤细胞可通过营养竞争消耗微环境中的氨基酸，从而抑制 T 细胞免疫；其次，氨基酸的有毒代谢物也可抑制 T 细胞功能；再次，氨基酸可以通过调节葡萄糖和脂质代谢来干扰 T 细胞 [66]。 在肿瘤组织中，由于存在高浓度的生长因子，导致细胞内关键信号分子如 c-Myc[67] 和 E2F[68] 被激活，氨基酸转运蛋白表达增加，促进肿瘤细胞对氨基酸的高摄取，导致氨基酸耗竭。而由于肿瘤微环境中的营养限制，免疫细胞、基质细胞和癌细胞必须为生长、增殖等生命活动而竞争营养。免疫细胞往往不适应营养竞争，从而导致免疫能力减弱。 肿瘤细胞对氨基酸的大量消耗伴随着有毒代谢物的产生，这些代谢物中很多都被证明对 T 细胞免疫具有抑制作用。比如色氨酸代谢产生的犬尿氨酸衍生物，一方面可以直接对免疫细胞产生毒性作用，抑制 T 细胞增殖，诱导 T 细胞凋亡，另一方面犬尿氨酸衍生物可引起细胞内氧化还原平衡的改变，并通过产生活性氧类诱导细胞凋亡 [69-70]。 氨基酸代谢对葡萄糖代谢的影响最为显著，氨基酸代谢后可转化为葡萄糖代谢途径中的底物，直接调节葡萄糖代谢；同时还能影响葡萄糖转运体的活性，间接影响葡萄糖代谢。氨基酸（如丙氨酸、色氨酸和丝氨酸）也可以转化为丙酮酸，丙酮酸在一定程度上促进糖酵解并产生乳酸，最终导致 T 细胞整体代谢的改变和功能的抑制 [71]。氨基酸代谢除了影响葡萄糖代谢外，还能调节脂质代谢。谷氨酰胺代谢产生 α-KG，参与脂肪酸的合成，丝氨酸和甘氨酸也是脂质合成的必要前体 [72]，而 T 细胞的快速增殖高度依赖于脂质为其提供细胞膜的成分。 随着氨基酸代谢和肿瘤微环境之间关系被逐步掲示，目前也提出了靶向氨基酸代谢和免疫治疗相结合的疗法，比如靶向氨基酸代谢和嵌合抗原受体T细胞免疫治疗以及与免疫检查点抑制剂联合疗法，在临床前实验以及临床试验中也取得了一些进展，但是整体来说通过靶向氨基酸代谢来开发新药还存在许多挑战。 3 靶向肿瘤脂质代谢 脂质代谢在癌症中被高度重编程，是癌症发生的重要标志之一。在癌症中，脂质代谢的改变通常表现为脂质生成增加、脂质摄取增加、脂滴的储存和动员增强 [73]。这些代谢改变通过提供膜脂成分、供能、调节细胞膜流动性、调控信号转导等多种方式促进肿瘤的增殖、侵袭和转移 [74]。表 7 列举了目前正处于临床研究的脂质代谢通路小分子抑制剂。 3.1 靶向脂肪酸代谢通路 癌细胞相较于普通细胞需要更多脂质以维持其存活和增殖。研究发现激活脂质合成途径是癌细胞增殖的必要条件，其中脂肪酸合成途径是癌细胞获取脂质的主要途径。脂肪酸合成酶（fatty acid synthetase，FAS）是脂肪酸合成途径中的关键酶，以 NADPH 依赖的方式催化棕榈酰辅酶 A 的合成，是脂肪酸合成关键的末端代谢酶。FAS 在肿瘤中表达显著上调，其上调不仅通过提高脂肪酸的合成代谢赋予肿瘤生存优势，还能够通过影响肿瘤微环境和癌症控制网络导致肿瘤的发展及恶性转化 [75]。 TVB-2640（denifanstat，ASC40）是首个经过临床测试的口服选择性强效可逆 FAS 抑制剂药物。该系列化合物通过抑制 FAS 调节脂肪酸合成通路，被用于相关适应证的研究，如丙型肝炎病毒感染、癌症、非酒精性脂肪性肝炎。TVB-2640 在癌症上的首次临床研究报告表明，其具有优异的口服生物利用度和安全性，体内半衰期约为 16 小时，试验中所有剂量水平的人体暴露量均高于小鼠临床前模型中预测的有效剂量 [76]。TVB-2640 在癌症上目前尚未有单药治疗策略的报道，但其与贝伐珠单抗的联合用药策略已进入Ⅲ期临床研究。TVB-2640 与贝伐珠单抗联合治疗复发性胶质母细胞瘤患者的Ⅱ期临床试验取得了积极的结果。临床数据显示，TVB-2640的安全性良好，大多数的不良事件强度为 1 级或 2级；药效方面，TVB-2640 与贝伐珠单抗联用的 6个月无进展生存率为 31.4%，相较贝伐珠单抗组的16% 具有统计学差异，贝伐珠单抗与 TVB-2640 联用的总缓解率为 56%，包括 17% 的完全应答和 39%的部分应答 [77]。此外，Sagimet Biosciences 公司的另一款 FAS 抑制剂 TVB-3567（ASC60）片剂也于2022 年在中国获批临床，用于晚期实体瘤的治疗。 3.2 靶向胆固醇代谢通路 胆固醇代谢是免疫稳态和癌症进展的重要检查点，部分研究已报道了胆固醇在癌症中的积累。胆固醇可以促进细胞的增殖、迁移和侵袭，胆固醇的摄入增加和合成水平上调易于导致肿瘤发生 [78]。癌细胞对胆固醇的需求增加，并且比正常细胞含有更多的脂筏，以满足对促肿瘤细胞信号蛋白的需求 [79]。 在胆固醇代谢通路中与癌症相关研究最多的靶点是 3-羟基-3-甲基戊二酰辅酶 A 还原酶（3-hydroxy-3-methylglutaryl-coenzyme A reductase，HMGCR），是胆固醇合成代谢中的关键限速酶，催化羟甲基戊二酰辅酶 A（hydroxylmethylglutaryl coenzyme A，HMG-CoA）还原为甲羟戊酸。除胆固醇外，甲羟戊酸下游胆固醇合成中间体也被发现对癌症的进展有关，如异戊二烯焦磷酸酯（isopentenyl pyrophosphate，IPP）、 香 叶 基 香 叶 基 焦 磷 酸 酯（geranylgeranyl pyrophosphate，GGPP）、 法 尼 基 焦 磷 酸（farnesyl pyropho-sphate，FPP）等，其中 GGPP 和 FPP 对各类蛋白的异戊二烯化翻译后修饰具有重要作用。 他汀类药物是 HMGCR 强效竞争性抑制剂，已有众多上市药物用于降低血浆胆固醇水平。近年来，他汀类药物的肿瘤抑制活性愈发受到关注。其抗癌机制多种多样，研究最广泛的是甲羟戊酸途径介导的机制。在该途径中，他汀类药物可通过耗尽GGPP 和 FPP 破坏关键蛋白的异戊二烯化来激活内在的凋亡途径，例如 Ras 和 Rho 的异戊二烯化降低进而延缓了肿瘤的进展 [80]；p53 突变可通过上调甲羟戊酸通路来破坏乳腺腺泡形态，从而发挥致癌作用，他汀类药物则抑制甲羟戊酸通路以发挥抑癌作用 [81]。此外，他汀类药物还被发现可通过调节自噬、诱导铁死亡、诱导焦亡、调节肿瘤微环境等方式抑制肿瘤发展进程 [80]。近年来，许多基于人群的观察性研究报告表明，与未使用他汀类药物的患者相比，癌症患者使用他汀类药物可降低死亡率 [82]。一些介入性临床数据也发现他汀类药物在抗癌治疗效果方面有积极作用，如辛伐他汀可提高局部晚期乳腺癌患者 5-氟尿嘧啶（5-fluorouracil，5-FU）、阿霉素（adriamycin）、环磷酰胺（cyclophosphamide）三药（FAC）联用的疗效，FAC 联合辛伐他汀的总缓解率为 90%，相较 FAC 组具有更好的活性和耐受性趋势 [83]；氟伐他汀对前列腺癌中肿瘤细胞凋亡具有积极作用 [84]；辛伐他汀可提高吉非替尼在吉非替尼耐药非小细胞肺癌患者亚组中的疗效，吉非替尼与辛伐他汀联合用药与吉非替尼单药组相比显示出更高的缓解率（38.5% vs 31.5%）和更长的无进展生存期（3.6 个月 vs 1.7 个月）[85]；他汀类药物与 PD-1抑制剂联合治疗恶性胸膜间皮瘤（malignant pleural mesothelioma，MPM）和晚期非小细胞肺癌（advanced non-small cell lung cancer，aNSCLC），在临床上有着更好的表现，在 2 种癌症中使用他汀类药物均展现出与 PD-1 抑制剂的协同效果，具有更高的缓解率（MPM：22% vs 6%；aNSCLC：40% vs 22%）和更长的无进展生存期（MPM：6.7 个月 vs 2.4 个月；aNSCLC：7.8 个月 vs 3.6 个月）[86]。这些研究展现了他汀类药物在抗癌治疗中的潜力，尤其是与其他抗癌药物联用。 3.3 靶向鞘脂合成通路 鞘脂代谢对癌症的发展也具有重要作用，其中神经酰胺（ceramide，Cer）、二氢神经酰胺、鞘氨醇（sphingosine，Sph）和 1-磷酸鞘氨醇（sphingosine-1-phosphate，S1P）可以调节肿瘤细胞死亡、增殖、耐药性以及宿主血管生成、炎症和免疫 [87]。鞘氨醇激酶（sphingosine kinase，SphK）是肿瘤中研究最多的鞘脂代谢靶点，SphK 有 SphK1 和 SphK2 亚型，二者为同工酶，催化 Sph 生成 S1P。SphK 在许多肿瘤细胞中过表达，并且研究证实抑制 SphK 可以杀死肿瘤细胞 [88]。 ABC294640（opaganib）为强效竞争性 SphK抑制剂，目前已进入临床试验阶段。临床前研究发现，ABC294640 在组织培养中可以降低 S1P 水平，抑制多种肿瘤细胞系的增殖、迁移并伴随微丝的消失；ABC294640 在降低 S1P 的同时升高 Cer的水平，抑制信号转导，促进多种癌细胞的自噬和（或）凋亡，并下调多种肿瘤细胞系中 c-Myc 的表达，还能降低前列腺癌细胞系中雄激素受体的表达；ABC294640 还能够抑制二氢神经酰胺去饱和酶1（dihydroceramide desaturase 1，DES1），DES1 的抑制与视网膜母细胞瘤蛋白磷酸化的减少和细胞周期进程的抑制有关，因此 ABC294640 是双功能抗肿瘤药物；ABC294640 与吉西他滨、索拉菲尼等多种药物联用在体外及动物模型中对多种癌症有积极的治疗效果 [88]。在一项针对 22 例晚期实体瘤患者的Ⅰ期临床研究中，ABC294640 表现出良好的耐受性，以 500 mg（bid）剂量给药达到了有效血药浓度，并将 500 mg（bid）的剂量水平确定为Ⅱ期临床推荐剂量；检测给药组患者体内 S1P 水平发现，给药后 12 小时血浆 S1P 达到最低值，250 mg/500 mg/750 mg组均表现出 50% 以上的 S1P 清除率，且血浆 S1P 在24 小时内恢复至基线水平；此外，在实体瘤反应评价标准可评估的患者中，1 例患者为部分缓解，6 例为病情稳定，9 例为最佳缓解 [89]。目前 ABC294640对胆管癌和前列腺癌的Ⅱ期临床试验正在进行中。 3.4 靶向脂质代谢在调控肿瘤免疫微环境中的应用前景 在肿瘤中，脂质代谢的重编程与肿瘤特殊微环境的形成相辅相成。一方面，肿瘤微环境的改变，如缺氧、酸中毒、营养物质改变，驱动了肿瘤细胞的脂质代谢重编程。肿瘤细胞的快速增殖消耗大量氧气，依赖氧气的脂肪酸分解代谢被抑制；在缺氧条件下，缺氧诱导因子（hypoxia-inducible factor，HIF）-1α 和-1β 被激活，可通过下调肉碱棕榈酰转氨酶-1、上调脂肪酸结合蛋白、上调低密度脂蛋白相关受体-1 的表达等方式抑制脂肪酸氧化并促进脂肪酸的摄取和储存 [90]。肿瘤微环境中乳酸的蓄积通过上调 CD36 和二酰基甘油酰基转移酶促进外源脂质摄取和脂滴的生成 [91]；激活 PI3K/AKT 通路并上调硬脂酰辅酶A去饱和酶-1促进脂肪酸的合成代谢[92]。肿瘤细胞的快速增殖导致肿瘤微环境中营养物质的快速消耗，为增加能量的供应，肿瘤细胞可通过分泌细胞因子诱导周围脂肪细胞释放游离脂肪酸供肿瘤细胞摄取 [93]。另一方面，脂质代谢的重编程也驱动肿瘤微环境转化为适应肿瘤发展的免疫抑制表型。肿瘤中脂质摄取增加会增加调节性 T 细胞、肿瘤相关巨噬细胞和 MDSC 中的脂质代谢水平，促进其免疫抑制功能 [94-96]；CD8+ T 细胞和自然杀伤细胞中CD36 的上调会抑制其抗肿瘤细胞因子释放并降低其对肿瘤细胞的杀伤能力 [97]。 尽管还未有通过调节脂质代谢以调节肿瘤微环境为机制的药物进入临床试验阶段，但众多研究表明该策略具有潜在的应用价值。 4 靶向肿瘤核酸代谢 核酸的合成代谢主要涉及嘌呤和嘧啶的合成，分为从头合成和补救合成途径。非增殖细胞中，从头合成途径活性通常很低或不存在，但在肿瘤细胞中，从头合成途径是必要的，目前大部分药物是针对肿瘤核酸的从头合成途径进行抑制。 一碳代谢作为从头合成中的重要原料提供途径，同样影响核酸代谢。该途径以四氢叶酸（tetrahydrofolic acid，THF）和 SAM 为主，涉及嘌呤与嘧啶合成时碳原子的添加过程。SAM 循环对 DNA 甲基化有重要作用，也是研究致癌原因的重要组成部分 [98]。以下将介绍嘧啶与嘌呤从头合成中关键代谢酶的相关临床在研药物，包括嘧啶合成中的二氢乳清酸脱氢酶（dihydroorotate dehydrogenase，DHODH）和胸苷酸合成酶（thymidylate，TS）、嘌呤合成中的甘氨酰胺核糖核苷酸甲酰转移酶（glycinamide ribonucleotide transformylase，GART） 和 5-氨 基-4-咪唑甲酰胺核糖核苷酸转化酶 /IMP 环 水 解 酶（5-amino-4-imidazolecarboxamide ribonucleotide transformylase/IMP cyclohydrolase，ATIC），以及一碳代谢中的二氢叶酸还原酶（dihydrofolate reductase，DHFR）和甲硫氨酸腺苷转移酶 2A（methionine adenosyltransferase 2A，MAT2A）。 4.1 靶向嘧啶从头合成途径 4.1.1 DHODH抑制剂 来氟米特是已上市的DHODH抑制剂，但其抑制活性较差，且具有明显副作用 [99]。RP-7214 为结构尚未披露的新型 DHODH 抑制剂，对 DHODH 有较好抑制效果（IC50=7.76 nmol·L-1），在多种癌细胞系中均表现出不同程度的抗增殖活性，能够抑制 AML 细胞生长（GI50=2~3.2 μmol·L-1），在 1 μmol·L-1 时诱导细胞凋亡，并导致 S 期细胞周期阻滞。此外，RP-7214 还能增强乳腺癌和结肠直肠癌细胞对化疗药物的敏感性 [100]。临床前药效研究显示，RP-7214 在 MV-4-11 小鼠移植瘤模型中作为单一药物或与阿糖胞苷联用均展现出抗肿瘤活性 [101]。RP-7214在针对健康受试者进行的Ⅰ期临床研究中具有良好的吸收和暴露量，且具有良好的安全性 [102]（见表 8）。 4.1.2 TS 抑制剂 TS 抑制剂中的 5-FU 是被广泛应用的抗癌药物（见表 9），它在体内被代谢为活性物 质 5'-氟 脱 氧 尿 苷 一 磷 酸（5'-fluorodeoxyuridine monophosphate，FdUMP）， 通 过 取 代 内 源 性 底物 2'- 脱氧尿苷-5'- 一 磷 酸（2'-deoxyuridine-5'-monophosphate，dUMP）竞争性地抑制 TS。但由于85% 的 5-FU 在肝脏中被二氢嘧啶脱氢酶降解 [103]，且在细胞内转移需要碱基转运体和复杂的酶处理来产生活性物质 [104]，导致克服 5-FU 限制和药理学挑战的药物设计极为重要。在近期研究中发现，NUC-3373 在临床试验中有着良好表现（见表 9）。NUC-3373 是 FdUMP 的前药，采用的是近年来核苷类药物常用的 ProTide 策略，将 FdUMP 中的磷酸基团设计合成相应的磷酰胺结构得到 NUC-3373。在胞内，NUC-3373 能够水解释放出具有活性的FdUMP，从而跳过了胸苷激酶将 5'-氟脱氧尿苷（5'-fluorodeoxyuridine，FUdR）磷酸化的限速步骤，使其能更快在胞内起效，并且能避免胸苷激酶的下调从而克服了 5-FU 原有的耐药问题 [105]。 NUC-3373 对实体肿瘤细胞系（HT-29，HCT-116，MDA-MB-231，SW- 620）、急性髓系白血病细胞（KG1a）均有较好抑制活性。其中 KG1a 对NUC-3373 最为敏感，与 5-FU（LC50=1.4 μmol·L-1）和 FUdR（LC50 =1.18 μmol·L-1）相比，NUC-3373 对KG1a 细胞的抑制活性约有 22 ~ 26 倍的提升（LC50 =0.053 μmol· L-1）[105]。在人结直肠癌小鼠异种移植模型中发现，NUC-3373 比 5-FU 具有更明显的肿瘤抑制作用。在临床研究中也发现，与 5-FU 相比，单药 NUC-3373 在晚期实体瘤患者中显示出良好的安全性和与药代动力学性质 [106]。 4.2 靶向嘌呤从头合成途径 在 嘌 呤 从 头 合 成 过 程 中，有 2 个关键酶—GART 和 ATIC，负责催化甲酰基的转移，为嘌呤提供结构所需的碳源。这 2 个步骤都对 N10-甲酰-四氢叶酸具有依赖性。 目前，针对 GART 与 ATIC 的大部分抑制剂都是模仿叶酸结构设计进而达到抑制效果的经典抗叶酸类药物，如培美曲塞、洛美曲索等。培美曲塞虽然对 GART 和 ATIC 都有抑制活性，但仅在低微摩尔范围内 [107]；而洛美曲索及 AG-2034（见表 10）虽然对 GART 有较好亲和力（Ki = 60 nmol·L-1，Ki =28 nmol· L-1），但遗憾的是这 2 种药物的临床试验均已终止。其中，AG-2034 退出临床试验的原因不仅是其在Ⅰ期临床中并未观察到抗肿瘤疗效，而且存在血小板减少症、中性粒细胞减少症和贫血等不良反应，以及药物代谢蓄积问题 [108]。 经典抗叶酸类药物在使用过程中往往会产生耐药性，产生耐药的主要机制是通过基因突变导致运输和多谷氨酸化机制的损害 [109]。相比之下，非经典的抗叶酸剂通过被动扩散穿透细胞，可克服主动摄取受损引起的抗性。代表性化合物 ATIC 抑制剂LSN-3213128（见表 10）在分子水平对 ATIC 有较好抑制活性（IC50 = 16 nmol · L-1)，对 NCI-H460 细胞的 IC50 达 19 nmol · L-1，且具有适中的药代动力学性质，后续在移植瘤模型中也表现出剂量依赖性的肿瘤生长抑制 [110]。尽管 LSN-3213128 尚未进入临床阶段，但是具有一定成药潜力，值得进一步关注。 4.3 一碳代谢中的抑制剂 在核苷酸代谢中，一碳代谢是重要的生物合成过程。由于增殖指数的增加，癌细胞对该生物过程表现敏感，因此靶向一碳代谢的药物长期以来一直被用作癌症治疗方法 [111]。对于嘧啶，一碳代谢的产物在 TS 催化下与尿嘧啶核苷酸（uridine monophosphate，UMP）反应生成胸苷一磷酸（thymidine monophosphate，TMP），直接影响嘧啶的从头合成过程；在嘌呤的从头合成过程，甲酰化四氢叶酸参与嘌呤的第 4 步与第 10 步甲酰基转移的过程。由于 5，10-亚甲基-四氢叶酸会在胞质内通过亚甲基四氢叶酸还原酶不可逆地还原为 5-甲基四氢叶酸，5-甲基四氢叶酸经 SAM 循环重新转为四氢叶酸，因此叶酸循环与 SAM 循环之间存在着相互联系 [112]（由于 SAM 循环部分已在前述甲硫氨酸代谢部分进行介绍，下面将不再重复阐述）。 DHFR 催化叶酸转化为四氢叶酸，是叶酸循环的起始步骤，也是临床上验证可治疗癌症的一碳代谢靶点。尽管现有许多上市的 DHFR 抑制剂（如甲氨蝶呤、三甲曲沙、雷替曲塞、培美曲塞），但这些药物都有口服利用度差、不良反应多（如黏膜炎、白细胞减少）[112] 等一系列问题。遗憾的是近年来，针对 DHFR 靶点的临床在研药物均以失败告终（见表 11），开发新型安全有效的 DHFR 抑制剂仍具有难度。 5 总结与展望 肿瘤代谢涉及多种营养物质与细胞生长信号通路，各种代谢途径彼此之间相对独立互补又相互关联代偿维持着氧化还原平衡，部分肿瘤的代谢产物又能进一步塑造肿瘤微环境实现免疫逃逸，或能作为信号分子对肿瘤代谢进行调控以增强代谢适应性。肿瘤拥有一个庞大且复杂的“生态体系”，并通过上述多种机制维持着稳态平衡。通过靶向肿瘤代谢破坏其稳态平衡是具有潜力的治疗策略。 目前，靶向肿瘤代谢治疗仍然存在一定瓶颈[8]。从药物开发角度来看，代谢酶小分子抑制剂开发本身便具有挑战性，一方面大部分代谢酶底物均为水溶性小分子，且在体内均以较高浓度存在，给底物竞争性抑制剂开发带来较大难度；另一方面，部分代谢酶在细胞中高度表达 [15]，如 Hela 细胞中，乳酸脱氢酶A（4 μmol·L-1），己糖激酶2（0.27 μmol·L-1）及 GLS1（0.07 μmol·L-1）均有较高表达，小分子难以完全抑制其活性。针对上述问题，寻找相应代谢酶的变构抑制剂则是较好的选择，能够在保证活性的同时提高靶点选择性；针对在胞内高表达的代谢酶，通过蛋白水解靶向嵌合体技术进行代谢酶的降解也是潜在的策略之一，但目前仍需要更多的实验进行验证。 从治疗策略来看，靶向肿瘤代谢也存在一些问题。首先，由于肿瘤的代谢适应性，单独调控代谢通路中的某一靶标，肿瘤仍能通过代谢重编程调整代谢网络，从而引发耐药等问题；且由于各条代谢通路代谢酶及代谢产物之间紧密联系，即使能够对某一代谢产物或酶做到完全抑制，也有可能对其他通路产生影响，产生与预期相反效果。其次，大部分肿瘤的代谢通路对正常细胞来说同样重要，难以做到较好的选择性，此外，部分免疫细胞与肿瘤细胞具有相似的代谢特征，在抑制肿瘤的同时也有可能抑制相应免疫细胞的活性从而使得治疗效果不显著。此外肿瘤代谢的异质性，即不同瘤种具有不同的代谢特征，也会使得单一代谢抑制可能仅对部分瘤种起效。 因此，针对肿瘤代谢治疗，一方面应当采用联合疗法，同时靶向多条代谢通路中的关键步骤，以破坏肿瘤代谢的代偿机制；或作为佐剂影响肿瘤环境增强其他药物的敏感度，这一点目前在靶向肿瘤代谢的临床试验中均有所体现 [8]；也可寻找相应代谢具有协同致死效应目的基因蛋白，以增强治疗效果。同时，针对不同肿瘤代谢特征应采取精准化治疗，例如在与 PD-1 抗体联用治疗时，可根据肿瘤的独特代谢特征选择相应的代谢抑制剂 [8] 改善疗效。另一方面，如果针对肿瘤代谢通路中某一关键酶进行靶向抑制后造成中间体的累积，有可能反而会激活其他旁路代谢；参考 PKM2 及 PDK 抑制剂临床小分子研究所带来的启发，尝试激动剂的开发或激活关键代谢酶，对拥堵的代谢通路进行“疏通”，从而减少代谢关键中间体的累积，减少旁路代谢流从而抑制肿瘤的生长，打破肿瘤原有的稳态环境，也未尝不是潜在的治疗策略。 参考文献: [1] Huynh C, Ryu J, Lee J, et al. 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Jan. 08, 2025 -- Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in cellular metabolism and pyruvate kinase (PK) activation pioneering therapies for rare diseases, today announced that the U.S. Food and Drug Administration (FDA) accepted the company’s supplemental New Drug Application (sNDA) for PYRUKYND® (mitapivat) for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia. The review classification for this application is Standard and the Prescription Drug User Fee Act (PDUFA) goal date is September 7, 2025. “Thalassemia is a rare, lifelong inherited blood disorder that causes chronic anemia and can lead to severe complications, including organ damage, stroke, and other serious health issues, with patients today having limited or no effective treatment options,” said Sarah Gheuens, M.D., Ph.D., chief medical officer and head of R&D at Agios. “We look forward to collaborating with the FDA in the coming months as they continue to review our application, with the goal of bringing PYRUKYND, a disease-modifying oral medication, to thalassemia patients regardless of their genotype or transfusion needs.” The sNDA is based on the results from the ENERGIZE and ENERGIZE-T Phase 3 trials evaluating mitapivat versus placebo in adults with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia, respectively. The ENERGIZE randomized clinical trial results were presented at the European Hematology Association 2024 Hybrid Congress in June 2024, and the ENERGIZE-T randomized clinical trial results were presented at the 66ᵗʰ American Society of Hematology Annual Meeting and Exposition in December 2024. U.S. INDICATIONPYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. Agios is the pioneering leader in PK activation and is dedicated to developing and delivering transformative therapies for patients living with rare diseases. In the U.S., Agios markets a first-in-class pyruvate kinase (PK) activator for adults with PK deficiency, the first disease-modifying therapy for this rare, lifelong, debilitating hemolytic anemia. Building on the company’s deep scientific expertise in classical hematology and leadership in the field of cellular metabolism and rare hematologic diseases, Agios is advancing a robust clinical pipeline of investigational medicines with programs in alpha- and beta-thalassemia, sickle cell disease, pediatric PK deficiency, myelodysplastic syndrome (MDS)-associated anemia and phenylketonuria (PKU). In addition to its clinical pipeline, Agios is advancing a preclinical TMPRSS6 siRNA as a potential treatment for polycythemia vera. For more information, please visit the company’s website at www.agios.com. The content above comes from the network. if any infringement, please contact us to modify.