Sapanisertib

BOSTON--(BUSINESS WIRE)--Sensei Biotherapeutics, Inc. (Nasdaq: SNSE) today reported financial results for the first quarter ended March 31, 2026, and provided a corporate update. “The first quarter of 2026 was transformational for the Company, with the acquisition of Faeth Therapeutics and the concurrent $200 million private placement in February, supported by a group of leading life sciences investors,” said Christopher Gerry, President & General Counsel of Sensei Biotherapeutics. “This acquisition and injection of new capital will allow us to advance PIKTOR, a differentiated multi-node pathway inhibitor, through key clinical milestones.” “New data across the industry continues to support the significant potential of multi-node inhibition of the PI3K/AKT/mTOR pathway,” said Anand Parikh, Chief Operating Officer of Sensei Biotherapeutics. “We believe PIKTOR is differentiated as an orally administered multi-node therapy specifically targeting PI3K-alpha, mTORC1 and mTORC2, with the potential to treat a variety of solid tumors. With our Phase 2 trial in advanced endometrial cancer expected to read out by the end of the year and the recent initiation of our Phase 1b/2 trial in advanced breast cancer, we are making great strides towards delivering the next generation of solid tumor therapies.” Clinical Program Highlights Acquired through the Faeth transaction, PIKTOR is now Sensei’s lead program. The investigational, proprietary, all-oral combination of serabelisib and sapanisertib is designed to inhibit multiple nodes of the PI3K/AKT/mTOR pathway through PI3K-alpha and dual mTORC1/2 targeting. In April 2026, the first patient was dosed in the Phase 1b/2 trial evaluating PIKTOR for the treatment of HR+/HER2- advanced breast cancer (Study FTH-PIK-101). Interim data from the trial is expected in 2027. The Phase 2 trial evaluating PIKTOR in advanced endometrial cancer (Study FTH-PIK-201) is on track to report topline data in the second half of 2026. First Quarter 2026 Financial Results Cash Position: Cash, cash equivalents and marketable securities were $202.8 million as of March 31, 2026, as compared to $21.2 million as of December 31, 2025. Research and Development (R&D) Expenses: R&D expenses were $18.0 million for the quarter ended March 31, 2026, compared with $3.7 million for the quarter ended March 31, 2025. The increase in R&D expenses was primarily attributable to the inclusion of Faeth R&D operations as well as one-time costs associated with the Faeth acquisition, partially offset by a reduction in the SNS-101 clinical trial costs. General and Administrative (G&A) Expenses: G&A expenses were $19.7 million for the quarter ended March 31, 2026, compared to $3.5 million for the quarter ended March 31, 2025. The increase in G&A expense was primarily attributable to one-time costs associated with the Faeth acquisition. Acquired In-Process Research and Development (Acquired IPR&D) Expenses: Acquired IPR&D expenses were $133.0 million for the quarter ended March 31, 2026. This represents the fair value of IPR&D assets obtained in connection with asset acquisition where the acquired IPR&D has no alternative future use as of the acquisition date. Net Loss: Net loss was $170.2 million, or $131.45 per basic and diluted share, for the quarter ended March 31, 2026, compared with a net loss of $6.9 million, or $5.45 per basic and diluted share, for the quarter ended March 31, 2025. Weighted-average common shares outstanding, basic and diluted, were 1,295,052 for the quarter ended March 31, 2026, compared with 1,259,531 for the quarter ended March 31, 2025. Condensed Statements of Operations (Unaudited, in thousands except share and per share data) For the Three Months Ended March 31, 2026 2025 Operating expenses: Research and development $ 17,957 $ 3,725 General and administrative 19,713 3,549 Acquired in-process research and development 132,957 — Total operating expenses 170,627 7,274 Loss from operations (170,627 ) (7,274 ) Total other income 391 410 Net loss (170,236 ) (6,864 ) Net loss per share, basic and diluted $ (131.45 ) $ (5.45 ) Weighted-average common shares outstanding, basic and diluted 1,295,052 1,259,531 Selected Condensed Balance Sheet Data (Unaudited, in thousands) March 31, 2026 December 31, 2025 Cash and cash equivalents $ 152,325 $ 8,668 Marketable securities 50,468 12,516 Total assets 205,381 22,902 Total liabilities 14,191 4,310 Series B redeemable convertible preferred stock 328,476 — Total stockholders’ (deficit) equity (137,286 ) 18,592 About Sensei Biotherapeutics Sensei Biotherapeutics, Inc. (Nasdaq: SNSE) is a clinical-stage biotechnology company focused on improving outcomes for cancer patients through multi-node inhibition of critical oncogenic pathways. Following the acquisition of Faeth Therapeutics, Sensei's lead program is PIKTOR, an investigational multi-node inhibitor of the PI3K/AKT/mTOR pathway in development for endometrial and breast cancer. Sensei is also completing a Phase 1/2 trial of solnerstotug, its V-domain Ig suppressor of T cell activation (VISTA) inhibitor, in patients with advanced solid tumors. Sensei intends to use its website as a means of disclosing material non-public information and for complying with its disclosure obligations under Regulation FD. For more information, please visit www.senseibio.com and follow the company on X @SenseiBio and LinkedIn. Cautionary Note Regarding Forward-Looking Statements Certain statements in this press release, other than purely historical information, may constitute "forward-looking statements" within the meaning of the federal securities laws, including for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. These forward-looking statements include, but are not limited to, express or implied statements relating to the company’s expectations, hopes, beliefs, intentions or strategies regarding the future including, without limitation, statements regarding: the expected benefits or opportunities following the acquisition of Faeth Therapeutics; expectations regarding or plans for the company’s pipeline, including the Phase 2 trial evaluating PIKTOR in advanced endometrial cancer and the expected timing for topline data, the Phase 1b/2 trial evaluating PIKTOR in HR+/HER2- advanced breast cancer and the expected timing for interim data, the completion of the remaining portion of the Phase 1/2 trial of solnerstotug and other research and development programs and the expected timing for key milestones; the potential benefits of PIKTOR, including its potential to treat a variety of solid tumors; expectations regarding the use of proceeds from the private placement and cash runway expectations therefrom, including such proceeds funding the company through key clinical milestones. In addition, any statements that refer to projections, forecasts or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking statements. The words "opportunity," "potential," "milestones," "pipeline," "can," "goal," "aim," "strategy," "target," "seek," "anticipate," "achieve," "believe," "contemplate," "continue," "could," "estimate," "expect," "intends," "may," "might," "plan," "possible," "predict," "project," "should," "will," "would" and similar expressions (including the negatives of these terms or variations of them) may identify forward-looking statements, but the absence of these words does not mean that a statement is not forward-looking. These forward-looking statements are based on current expectations and beliefs concerning future developments and their potential effects. There can be no assurance that future developments affecting the company will be those that have been anticipated. These forward-looking statements involve a number of risks, uncertainties (some of which are beyond the company’s control) or other assumptions that may cause actual results or performance to be materially different from those expressed or implied by these forward-looking statements. These risks and uncertainties include, but are not limited to those uncertainties and factors described under the heading "Risk Factors" and "Summary of Risk Factors" in the company’s Quarterly Report on Form 10-Q, filed with the Securities and Exchange Commission (the "SEC") on May 14, 2026, as well as discussions of potential risks, uncertainties, and other important factors included in other filings by the company from time to time, as well as risk factors associated with companies, such as Faeth, that operate in the biotechnology industry. Should one or more of these risks or uncertainties materialize, or should any of the company’s assumptions prove incorrect, actual results may vary in material respects from those projected in these forward-looking statements. Nothing in this press release should be regarded as a representation by any person that the forward-looking statements set forth herein will be achieved or that any of the contemplated results of such forward-looking statements will be achieved. You should not place undue reliance on forward-looking statements in this press release, which speak only as of the date they are made and are qualified in their entirety by reference to the cautionary statements herein. The company does not undertake or accept any duty to release publicly any updates or revisions to any forward-looking statements. This press release does not purport to summarize all of the conditions, risks and other attributes of an investment in the company.

近期《Nature Reviews Drug Discovery》发表综述，系统梳理小分子激酶调节剂的现代设计策略，对比正构抑制、别构调节、分子诱导接近三大核心技术，全面分析三类策略的机制、优势、局限、耐药、临床案例与未来方向。一、激酶药物发现的现状与挑战 激酶规模：人类激酶组包含约500种激酶（Manning et al., 2002），占人类基因的2%，调控约30%蛋白质组的磷酸化。 临床成就：截至2025年12月，FDA已批准100种小分子激酶抑制剂（全球超过130种），每年新增约5-10种（Roskoski, 2025；Mullard, 2025）。 未满足需求：尽管成功，大量疾病相关激酶（尤其假激酶、支架蛋白）仍难以靶向。 三大挑战： 选择性：ATP结合口袋高度保守，传统抑制剂易脱靶。 非催化功能：许多激酶通过支架或结构作用驱动疾病（如HER3、NEK7、IRAK4），ATP抑制剂无法阻断。 耐药性：靶向突变、旁路激活、谱系转化导致疗效衰减。二、激酶分类（Kinase classification）2.1 基于底物类型 蛋白激酶（Ser/Thr、Tyr、双特异性、非典型） 脂质激酶（PI3K、PIKfyve等） 碳水化合物激酶 其他小分子激酶2.2 基于序列进化（人类激酶组八大分支） AGC、CAMK、CK1、CMGC、STE、TK、TKL、RGC。结构上，所有激酶共享一个双叶催化结构域，包含： N叶：β-折叠 + C-螺旋（αC-helix） C叶：α-螺旋丰富，含活化环（activation loop）和DFG基序（Asp-Phe-Gly）2.3 基于功能分类 临床获批的激酶抑制剂时间线三、激酶正构抑制剂（Orthosteric inhibitors）3.1 机制与结构基础 结合在ATP结合口袋，与ATP竞争，阻断磷酸转移。 典型的氢键与铰链区（hinge region）残基相互作用。 代表性药物：伊马替尼、吉非替尼、奥希替尼、palbociclib、ibrutinib等。3.2 实现选择性的工程策略3.2.1 利用守门员残基（gatekeeper） 激酶ATP口袋后部有一个保守残基，大小不同（小如Thr，大如Met）。 设计抑制剂适应小门残基而排斥大门残基可获得选择性。 经典应用：化学遗传学方法（Bishop et al., 2000）通过突变守门员创造“激酶敏感等位基因”。3.2.2 构象偏好 伊马替尼：结合“DFG-out”非活性构象，打开一个疏水后口袋。只有ABL、KIT、PDGFR等少数激酶能稳定采用此构象，因此伊马替尼选择性高（Schindler et al., 2000）。 结合动力学：两步骤诱导契合（induced-fit），解离慢（off-rate低），延长停留时间。3.2.3 共价抑制剂 机制：可逆识别 + 共价键形成（如丙烯酰胺与半胱氨酸反应）。 第一代BTK抑制剂伊布替尼：靶向Cys481，但也会抑制TEC家族（ITK、TEC）和部分EGFR家族，导致脱靶毒性。 第二代：阿卡替尼（acalabrutinib）使用反应性较低的丁炔酰胺，提高选择性。 耐药：C481S突变废除共价结合，催生非共价BTK抑制剂（如pirtobrutinib）。 高选择性案例：lirafugratinib (RLY-4008) 通过长时程分子动力学模拟发现FGFR1与FGFR2的P-loop动态差异，设计共价靶向FGFR2的Cys491，对FGFR1和FGFR4分别实现250倍和5000倍选择性（Schönherr et al., 2024; Subbiah et al., 2023）。 3.3 正构抑制剂的局限性 占有率驱动药理学：需持续高浓度维持抑制，停药后功能恢复。 临床要求：通常需>90%的靶点抑制（BRAF、BTK、EGFR等），导致高剂量和毒性。 共价抑制剂可延长停留时间，但新蛋白合成后需重新结合。 无法靶向非催化功能： HER3（假激酶）：作为EGFR的二聚化伙伴和底物，驱动耐药，抑制EGFR激酶活性不阻断HER3的支架功能（Sergina et al., 2007）。 NEK7：无激酶活性，作为NLRP3炎症小体组装支架，ATP抑制剂无效。 IRAK4：在Mydosome复合物中发挥支架作用，ATP抑制剂仅部分抑制通路。 耐药突变： 守门员突变：EGFR T790M（对吉非替尼耐药）、ABL T315I（对伊马替尼耐药） 溶剂前沿突变：ALK G1202R（对克唑替尼耐药） P-loop突变：ABL G250E、Y253H 活化环突变：FLT3 D835Y 铰链区突变：ABL F317L αC-螺旋突变：ALK F1174L 半胱氨酸突变：BTK C481S（共价抑制剂耐药） 靶向激酶的临床正构、变构及分子胶实例四、变构激酶调节剂（Allosteric modulators）4.1 定义与优势 结合于ATP口袋以外的位点（调控域、自抑制位点、蛋白-蛋白界面） 优势：更高选择性、可靶向非催化功能、可能绕过ATP位点耐药突变、减少脱靶毒性。 限制：最大效应（Emax）可能有限（天花板效应），部分变构调节剂曝光-响应平坦。4.2 代表性案例4.2.1 曲美替尼（Trametinib，MEK1/2变构抑制剂） 结合于MEK活化环附近的变构口袋，锁定非活性构态。 与支架蛋白KSR1形成复合物时，药物停留时间显著延长（Gilmartin et al., 2011）。 已获批用于BRAF突变黑色素瘤等。4.2.2 阿西米尼（Asciminib，ABL变构抑制剂） 结合于ABL的肉豆蔻酰口袋（myristoyl pocket），稳定非活性构型。 对T315I“守门员”突变有效，可克服ATP位点抑制剂（伊马替尼、达沙替尼等）耐药。 2021年获FDA批准用于CML（Wylie et al., 2017; Yeung et al., 2022）。4.2.3 雷帕霉素（Rapamycin）——变构与分子胶的交叉 结合FKBP12，形成的复合物再结合mTOR的FRB结构域，变构抑制mTORC1。 不抑制mTORC2，选择性独特（Saxton & Sabatini, 2017）。 既是变构抑制剂，也是原型分子胶。4.2.4 共价变构抑制剂 案例：AKT1(E17K)选择性抑制剂（Craven et al., 2025）。 E17K突变在PH结构域，破坏自抑制构象。 水杨醛衍生物与AKT1(E17K)形成共价键并螯合锌离子，实现对突变体的选择性抑制，避免对AKT2抑制所致高血糖。4.3 变构位点的发现方法 片段筛选：NMR、晶体学（Ludlow et al., 2015） ATP位点掩蔽下的文库筛选：DEL、HTS（Iqbal et al., 2025） 共价/化学蛋白质组学（Backus et al., 2016; Ostrem et al., 2013） 生物物理：氢氘交换质谱（HDX）、LiP-MS、DSF（Krishnamurthy et al., 2025） 计算预测：PocketMiner（Meller et al., 2023）等深度学习工具。五、诱导临近策略（Induced proximity）5.1 基本原理 利用小分子强制拉近靶蛋白与效应蛋白，产生药理后果。 效应蛋白可以是E3泛素连接酶（降解）、磷酸酶（失活）、激酶（修饰）、支架蛋白（隔离）等。 历史原型：雷帕霉素（FKBP12→mTOR）、环孢素（cyclophilin→calcineurin）。5.2 诱导临近相比正构抑制的优势 选择性更高：利用非保守口袋或复合表面。 可靶向支架和非催化功能：降解可彻底消除支架功能。 事件驱动药理学：短暂结合即可持续效应（降解后需新蛋白合成恢复），允许间歇给药。 克服结合位点突变：降解绕过突变；RIPTAC可绕过ATP位点突变。 可靶向无口袋蛋白：分子胶通过复合表面识别新底物。 实现不同功能：招募不同效应酶实现降解、磷酸化、乙酰化等。六、蛋白降解靶向嵌合体（PROTACs）6.1 机制 同时结合靶蛋白和E3连接酶（常用CRBN或VHL），诱导泛素化及蛋白酶体降解。 催化型工作：一个降解剂分子可降解多个靶蛋白。6.2 BTK降解剂 关键数据：对C481S突变BTK有效，克服伊布替尼耐药；Nurix的NX-5948在CLL中显示快速持久缓解（Omer et al., 2025）。6.3 IRAK4降解剂（KT-474 / KT-485） 背景：IRAK4在Mydosome中发挥支架功能，ATP抑制剂（如zimilovseritib）在化脓性汗腺炎和类风湿关节炎中疗效有限（Kimball et al., 2024）。 KT-474：CRBN招募PROTAC，在外周血单核细胞中实现>90%降解，在病变皮肤中几乎完全消除IRAK4，抑制IL-6等细胞因子（Ackerman et al., 2023）。 临床：在化脓性汗腺炎中减少炎性病变，耐受良好。2025年Sanofi决定以下一代KT-485替代，预计2026年进入临床。 意义：可能成为首个在免疫领域取得概念验证的PROTAC。6.4 BRAF(V600E)降解剂（CFT1946） 靶向BRAF(V600E/K)，克服二聚化和剪接变异导致的耐药。 2023年进入临床I期，部分缓解数据（Vieito et al., 2024）。 2025年5月C4 Therapeutics因战略调整终止开发，寻求合作伙伴。6.5 EGFR降解剂（CFT8919） 靶向L858R及C797S耐药突变（奥希替尼耐药）。 临床前对T790M/C797S双突变有效。2023年进入临床，通过授权合作在China开发。6.6 挑战与考量 靶点安全性：降解彻底消除蛋白，可能较抑制剂有更大毒性风险（如WEE1必需基因）。 理化性质：PROTAC分子量大（~800-1200 Da），需优化口服吸收和渗透性（Hornberger & Araujo, 2023）。 耐药：可通过E3连接酶下调、蛋白酶体饱和、degron突变等产生。 激酶PROTACs及分子胶降解剂的实例七、分子胶降解剂（Molecular glue degraders）7.1 机制 单价小分子（通常结合E3连接酶CRBN），重塑其表面，使其识别并降解新底物（neosubstrate）。 经典案例：沙利度胺及其类似物（来那度胺、泊马度胺）降解IKZF1/3，治疗多发性骨髓瘤。7.2 CRBN谷酰亚胺类分子胶的底物识别规律 G-loop degron：激酶N端β-发夹结构中的特定序列（如CK1α、WEE1、NEK7）。 亦有非G-loop degron（如ALK依赖D1389）。 内源性底物：C-末端环状酰亚胺（Asn/Gln自发环化），提示CRBN可能参与清除受损蛋白（Xu et al., 2025）。7.3 代表性案例7.3.1 CK1α降解剂：CC-91633 / BMS-986397（图4d） 来那度胺可降解CK1α但伴随IKZF1/3降解。 CC-91633：选择性降解CK1α（通过G-loop），避免IKZF1/3降解，在del(5q) MDS和AML中稳定p53，诱导凋亡（Mortensen et al., 2024）。 临床I期初步耐受良好。7.3.2 WEE1降解剂：BMS-986463 WEE1是G2/M检查点关键激酶，ATP抑制剂（如AZD1775）因毒性和耐药受限。 BMS-986463通过CRBN识别WEE1 G-loop，降解程度深于抑制，实现更持久肿瘤消退（Riggs et al., 2025）。 2024年进入临床I期（NCT06476808）。7.3.3 NEK7降解剂：MRT-8102 NEK7是假激酶，作为NLRP3炎症小体支架蛋白，无激酶活性。 MRT-8102（Monte Rosa）：口服生物利用度，在人和小鼠巨噬细胞中降解NEK7，抑制IL-1β/IL-18释放（Wible et al., 2025）。 2025年进入临床I期（NCT07119125），但NEK7在灵长类中可能非必需，疗效可能依赖上下文。7.3.4 ALK降解剂：CM-701 / CM-486 靶向ALK融合蛋白，包括G1202R、L1196M等耐药突变。 识别非G-loop degron（D1389关键），突变该残基则降解消除。 CM-486具脑穿透性，用于CNS转移（Wang et al., 2025 AACR）。7.3.5 CDK2降解剂：MRT-51443等 CDK4/6抑制剂耐药常伴随cyclin E–CDK2激活。 MRT-51443：高选择性降解CDK2，与CDK4/6抑制剂+氟维司群协同，在ER+乳腺癌模型中诱导肿瘤退缩而非仅稳定（Gkountela et al., 2025 AACR）。 采用非G-loop的新degron界面。7.3.6 Cyclin K降解剂 → CT-7439 (samuraiciclib) (R)-CR8：意外发现其结合CDK12并招募DDB1-CUL4复合物，导致cyclin K降解（Slabicki et al., 2020）。 CT-7439（Carrick Therapeutics）：临床期分子，兼具CDK12抑制与cyclin K降解，下调DNA损伤应答基因，与PARP抑制剂协同（Bahl et al., 2025）。2023年IND获批，2024年进入临床I期。7.4 降解剂临床进展总结 BTK：多个PROTAC进入临床，BGB-16673进入III期 IRAK4：KT-474完成I期，升级至KT-485 CK1α、WEE1、NEK7、CDK2、cyclin K：分子胶降解剂处于I/II期 BRAF(V600E)降解剂终止开发；EGFR降解剂仍在早期 异二价与单价邻近诱导调节剂八、非降解性诱导临近策略8.1 雷帕霉素范式拓展：RapaLink-1 和 RapaBlock 背景：雷帕霉素选择性抑制mTORC1，但临床上对肿瘤效力不足。 RapaLink-1：双功能分子（分子量~1800 Da），包含： mTOR ATP竞争性抑制剂（如INK128） 雷帕霉素类似物（结合FKBP12） 连接两个配体，同时占据ATP位点和FKBP12-FRB位点。 效果：停留时间显著延长，在胶质母细胞瘤模型中诱导肿瘤退缩（而传统抑制剂仅停滞）（Rodrik-Outmezguine et al., 2016; Zhang et al., 2022）。 RapaBlock：一个不能穿过血脑屏障的FKBP12配体。 在外周组织中占据FKBP12，阻止RapaLink-1锚定，减少全身毒性。 在脑内，RapaBlock无法进入，RapaLink-1仍可结合FKBP12，实现脑组织选择性mTOR抑制。 临床前模型中，RapaLink-1 + RapaBlock组合在有效抑制脑内肿瘤的同时，减轻外周mTOR抑制相关毒性（高血糖、免疫抑制等）。8.2 RIPTACs（Regulated Induced Proximity Targeting Chimeras） 原理：异双功能分子，一端结合肿瘤富集抗原（如突变p53、AR、HER2等），另一端结合必需蛋白（如PLK1、BRD4、CDKs等）。只有在肿瘤细胞中（靶蛋白高表达时）形成三元复合物，抑制必需蛋白，导致肿瘤细胞死亡；正常细胞因靶蛋白低表达而豁免。 类比：类似“细胞内抗体药物偶联物”。必需蛋白扮演“有效载荷”角色。 关键要求：肿瘤细胞中靶蛋白丰度需远超必需蛋白，确保选择性。 概念验证： FKBP配体 + CDK抑制剂：在工程化表达FKBP12的细胞中实现约1000倍选择性杀伤（Raina et al., 2024）。 p53-01：结合突变p53（Y220C）的小分子与PLK1抑制剂偶联，在p53突变细胞中富集毒性（Sadagopan et al., 2025）。 HLD-0915（Halda Therapeutics）：口服、靶向雄激素受体和BRD4的RIPTAC，在临床I期转移性去势抵抗前列腺癌患者中显示初步抗肿瘤活性（Hahn et al., 2025）。 耐药潜在机制：肿瘤抗原丢失或下调、必需蛋白突变或过表达、复合物形成所需化学计量失衡。 诱导邻近激酶调节剂的典型实例九、耐药性：所有模态的共同挑战9.1 以EGFR为范例的三种耐药类型 靶向突变： 第一/二代抑制剂（吉非替尼）→ T790M（守门员） 第三代（奥希替尼）→ C797S（共价结合失） 第四代抑制剂需应对双突变等复杂情况。 旁路信号激活：MET扩增、HER2/AXL激活、KRAS/BRAF突变。 谱系可塑性：EGFR突变肺腺癌转化为小细胞肺癌（SCLC），丧失EGFR依赖性（Marcoux et al., 2019）。9.2 不同模态的耐药特征 9.3 选择性 vs. 多药理学 历史上广谱激酶抑制剂（如索拉非尼、舒尼替尼）通过多靶点获得临床成功。 但无指导的广谱性增加风险（脱靶毒性、PK/PD复杂）。 推荐方法：明确最小必要靶点集，优先使用高选择性药物的合理组合，而非单分子多靶点（如BRAFi + EGFR抗体用于BRAF突变结直肠癌，CDK4/6i + 内分泌治疗用于乳腺癌）。十、未来方向10.1 扩展可药激酶组 当前100种抑制剂主要靶向TK、AGC、CMGC、CK1、TKL等少数家族，大量“暗激酶”无合适化学探针。 假激酶（如HER3、NEK7、MLKL）已通过诱导临近策略开始变得可药。10.2 激酶激活剂（Kinase activators） 激活有益激酶（如AMPK用于代谢疾病、Parkin用于神经保护）。 直接AMPK激活剂PXL770已进入II期临床（Cusi et al., 2021）。 仍需更多真正直接、选择性的激酶激活剂。10.3 生物分子凝聚体与“相感知”药物 激酶常在液-液相分离凝聚体中信号转导，影响底物选择性、催化速率和药物可及性（Sang et al., 2022）。 凝聚体可改变药物局部浓度、屏蔽活性位点。 未来可设计“相感知”分子，在特定凝聚体中富集或发挥作用。10.4 多模态融合与组合疗法 双功能分子：抑制+降解（如部分BTK降解剂仍保留抑制活性） 条件依赖性切换：某些分子胶在高浓度下可能同时抑制其他激酶 组合： 正构抑制剂 + 变构抑制剂（如ABL抑制剂 + asciminib） 抑制剂 + 降解剂（如CDK4/6抑制剂 + CDK2降解剂） RIPTAC + 免疫检查点抑制剂（协同增强抗肿瘤免疫） 激酶药物研发的前沿机遇：研究人员已发现针对多种类别激酶的选择性小分子调节剂，这些激酶包括“暗激酶组”中的成员，以及那些化学调节剂仍难以鉴定的激酶（例如许多肿瘤抑制性激酶）。未来研发方向还包括新型邻近诱导剂、突变选择性抑制剂，以及克服耐药性的策略——这些策略适用于药理学已明确作用靶点及已用药治疗的激酶组。下图展示了美国食品药品监督管理局（FDA）批准的针对所列激酶家族及靶点的药物数量（数据截至2025年12月）。十一、结论 激酶药物发现正在从“靶向哪个激酶”转向“如何最佳调节它”。 正构抑制剂仍是基石，但受限于选择性、非催化功能和耐药。 变构调节剂提供更高选择性和绕过ATP位点突变的能力。 诱导临近策略（降解剂、分子胶、RIPTAC）彻底改变了药理学范式，实现事件驱动、催化型、可编程的功能干预。 耐药是所有模态的共同挑战，需要通过模态选择、合理组合和动态监测来管理。 未来10年，激酶药物将更加精确、条件依赖、多功能集成，有望覆盖更广泛的疾病（癌症、免疫、神经、代谢）。 https://doi.org/10.1038/s41573-026-01411-9