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Article(id=1201177210083304338, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201177206518145841, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-0472, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1681660800000, receivedDateStr=2023-04-17, revisedDate=1692547200000, revisedDateStr=2023-08-21, acceptedDate=null, acceptedDateStr=null, onlineDate=1764312563677, onlineDateStr=2025-11-28, pubDate=1704988800000, pubDateStr=2024-01-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764312563677, onlineIssueDateStr=2025-11-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764312563677, creator=13701087609, updateTime=1764312563677, updator=13701087609, issue=Issue{id=1201177206518145841, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='1', pageStart='1', pageEnd='268', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764312562826, creator=13701087609, updateTime=1764312760268, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1201178034725417827, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201177206518145841, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1201178034725417828, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201177206518145841, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=61, endPage=75, ext={EN=ArticleExt(id=1201177210553066414, articleId=1201177210083304338, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Kinase modulators approved by FDA in 2022, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

The FDA approved a total of 37 new drugs in 2022, including 22 new molecular entities and 15 new biological products. This is the year with the lowest number of new drugs approved by the FDA since 2017. Among these approved drugs, 21 new drugs belong to the "first-in-class" category, accounting for 56% of the total approved drugs, which is the highest ratio in the past 10 years. Among the drugs approved in 2022, there are 5 small molecule kinase modulators, including the tyrosine kinase 2 (TYK2) allosteric inhibitor deucravacitinib, the first oral pyruvate kinase (PK) activator mitapivat, the Janus kinase 1 (JAK1) selective inhibitor abcrocitinib, the JAK2 selective inhibitor pacritinib and the broad-spectrum fibroblast growth factor receptor (FGFR) inhibitor futibatinib. This review briefly describes the discovery background, research and development process, synthesis routes and clinical efficacy and safety of small molecule kinase modulators approved by the FDA in 2022, hoping to provide ideas and methods for further research on kinase modulators.

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美国食品药品监督管理局(FDA) 在2022年共计批准上市37种新药, 包含22个新分子实体和15个新生物制品, 这也是2017年以来, 美国FDA批准新药上市数量最少的一年。这些获批的药物中共有21种属于首创性(first-in-class) 药物范畴, 占总获批药物的56%。在2022年获批的药物中, 有5种药物属于小分子激酶调节剂, 包括酪氨酸激酶2 (tyrosine kinase 2, TYK2) 变构抑制剂氘可来昔替尼(deucravacitinib)、首款口服丙酮酸激酶(pyruvate kinase, PK) 激活剂米他匹伐(mitapivat)、Janus激酶1 (Janus kinase 1, JAK1) 选择性抑制剂阿布昔替尼(abcrocitinib)、Janus激酶2 (Janus kinase 2, JAK2) 选择性抑制剂帕克替尼(pacritinib) 以及广谱成纤维细胞生长因子受体(fibroblast growth factor receptor, FGFR) 抑制剂福巴替尼(futibatinib)。本文通过浅析2022年FDA批准的小分子激酶调节剂的研发背景、研发思路、合成路线以及临床疗效和安全性等, 以期望为更多激酶调节剂的研究提供思路与方法。

, correspAuthors=陆小云, authorNote=null, correspAuthorsNote=
*陆小云, E-mail:
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The X-ray crystal structure of abcrocitinib complexed with JAK1 (PDB ID: 6BBU) and JAK2 (PDB ID: 6BBV) (B). The JAK1 and JAK2 are shown by cyan and green cartoon respectively. 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Drug (Brand name)SponsorStructureTargetIndication
Abcrocitinib (Cibinqo)PfizerJAK1Atopic dermatitis
Pacritinib (Vonjo)CTI BiopharmaJAK2/IRAK1/GSF1RMyelofibrosis
Deucravacitinib (Sotyktu)Bristol Myers SquibbTYK2Plaque psoriasis
Futibatinib (Lytgobi)Taiho Oncologypan-FGFRFGFR2-aberrant intrahepatic cholangiocarcinoma
Mitapivat (Pyrukynd)Agios PharmaceuticalsPyruvatehemolytic anemia in pyruvate kinase deficiency
), ArticleFig(id=1201177219717620373, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201177210083304338, language=CN, label=Table 1, caption=

Small molecule kinase inhibitors approved by FDA in 2022

, figureFileSmall=null, figureFileBig=null, tableContent=
Drug (Brand name)SponsorStructureTargetIndication
Abcrocitinib (Cibinqo)PfizerJAK1Atopic dermatitis
Pacritinib (Vonjo)CTI BiopharmaJAK2/IRAK1/GSF1RMyelofibrosis
Deucravacitinib (Sotyktu)Bristol Myers SquibbTYK2Plaque psoriasis
Futibatinib (Lytgobi)Taiho Oncologypan-FGFRFGFR2-aberrant intrahepatic cholangiocarcinoma
Mitapivat (Pyrukynd)Agios PharmaceuticalsPyruvatehemolytic anemia in pyruvate kinase deficiency
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2022年FDA批准的激酶调节剂浅析
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郑绚 , 陆小云 *
药学学报 | 综述 2024,59(1): 61-75
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药学学报 | 综述 2024, 59(1): 61-75
2022年FDA批准的激酶调节剂浅析
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郑绚, 陆小云*
作者信息
  • 暨南大学药学院, 广东 广州 510632

通讯作者:

*陆小云, E-mail:
Kinase modulators approved by FDA in 2022
Xuan ZHENG, Xiao-yun LU*
Affiliations
  • College of Pharmacy, Jinan University, Guangzhou 510632, China
出版时间: 2024-01-12 doi: 10.16438/j.0513-4870.2023-0472
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美国食品药品监督管理局(FDA) 在2022年共计批准上市37种新药, 包含22个新分子实体和15个新生物制品, 这也是2017年以来, 美国FDA批准新药上市数量最少的一年。这些获批的药物中共有21种属于首创性(first-in-class) 药物范畴, 占总获批药物的56%。在2022年获批的药物中, 有5种药物属于小分子激酶调节剂, 包括酪氨酸激酶2 (tyrosine kinase 2, TYK2) 变构抑制剂氘可来昔替尼(deucravacitinib)、首款口服丙酮酸激酶(pyruvate kinase, PK) 激活剂米他匹伐(mitapivat)、Janus激酶1 (Janus kinase 1, JAK1) 选择性抑制剂阿布昔替尼(abcrocitinib)、Janus激酶2 (Janus kinase 2, JAK2) 选择性抑制剂帕克替尼(pacritinib) 以及广谱成纤维细胞生长因子受体(fibroblast growth factor receptor, FGFR) 抑制剂福巴替尼(futibatinib)。本文通过浅析2022年FDA批准的小分子激酶调节剂的研发背景、研发思路、合成路线以及临床疗效和安全性等, 以期望为更多激酶调节剂的研究提供思路与方法。

研发背景  /  研发思路  /  合成路线  /  临床疗效和安全性

The FDA approved a total of 37 new drugs in 2022, including 22 new molecular entities and 15 new biological products. This is the year with the lowest number of new drugs approved by the FDA since 2017. Among these approved drugs, 21 new drugs belong to the "first-in-class" category, accounting for 56% of the total approved drugs, which is the highest ratio in the past 10 years. Among the drugs approved in 2022, there are 5 small molecule kinase modulators, including the tyrosine kinase 2 (TYK2) allosteric inhibitor deucravacitinib, the first oral pyruvate kinase (PK) activator mitapivat, the Janus kinase 1 (JAK1) selective inhibitor abcrocitinib, the JAK2 selective inhibitor pacritinib and the broad-spectrum fibroblast growth factor receptor (FGFR) inhibitor futibatinib. This review briefly describes the discovery background, research and development process, synthesis routes and clinical efficacy and safety of small molecule kinase modulators approved by the FDA in 2022, hoping to provide ideas and methods for further research on kinase modulators.

discovery background  /  research and development process  /  synthesis route  /  clinical efficacy and safety
郑绚, 陆小云. 2022年FDA批准的激酶调节剂浅析. 药学学报, 2024 , 59 (1) : 61 -75 . DOI: 10.16438/j.0513-4870.2023-0472
Xuan ZHENG, Xiao-yun LU. Kinase modulators approved by FDA in 2022[J]. Acta Pharmaceutica Sinica, 2024 , 59 (1) : 61 -75 . DOI: 10.16438/j.0513-4870.2023-0472
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蛋白激酶是细胞生命活动的重要信使, 可催化将ATP末端的γ-磷酸基团转移至底物上影响底物的结构和活性, 从而传递各种胞外信号。研究表明在人体中已发现超过500种蛋白激酶, 且编码具有激酶活性蛋白的基因约占人类基因组的2%。蛋白激酶在调节细胞生命过程中发挥重要作用, 主要影响细胞的增殖、凋亡、迁移以及相关炎症及代谢等。激酶表达量的改变或基因的突变和融合驱动各种肿瘤、自身免疫和炎症性疾病、退行性疾病和传染病等的发生[1]。
自2001年第一个激酶抑制剂伊马替尼获批用于治疗慢性粒细胞白血病以来, 激酶调节剂的研究取得了重大进展, 截至2022年12月31日, 美国FDA已经批准75种小分子激酶调节剂上市(主要为抑制剂), 另有约500个小分子激酶调节剂处于临床试验阶段。尽管如此, 该领域的研究仍存在许多挑战和尚未满足的临床需求, 其中较突出的是获得性耐药、选择性差、适应症单一等, 亟需开发新型激酶调节剂。
在2022年, 美国FDA共计批准上市新药37个, 其中包含22个新分子实体和15个新生物制品[2]。在获批的化学药物中, 有5种为小分子激酶调节剂如表 1所示。其中3种为Janus激酶(Janus kinase, JAK) 抑制剂, 包括用于治疗患有复发性中度至重度特应性皮炎(atopic dermatitis, AD) 的成人患者的JAK1选择性抑制剂阿布昔替尼、用于治疗伴有严重血小板减少症的骨髓纤维化(myelofibrosis, MF) 患者的JAK2选择性抑制剂帕克替尼以及用于治疗适合全身治疗或光疗的中度至重度斑块型银屑病成人患者的首个口服高选择性酪氨酸激酶2 (tyrosine kinase 2, TYK2) 变构抑制剂氘可来昔替尼; 另外两款则是用于治疗既往接受过治疗的、不可切除局部晚期或转移性肝内胆管癌(intrahepatic cholangiocarcinoma, ICC), 伴有FGFR2基因重排(包括基因融合) 的成人患者的广谱FGFR抑制剂福巴替尼以及患有丙酮酸激酶缺乏症(pyruvate kinase deficiency, PKD) 且出现溶血性贫血的成人患者的PK激活剂米他匹伐。
大多数已获批的激酶调节剂通过占据ATP结合位点直接靶向激酶的催化功能, 然而由于人类激酶ATP口袋序列和结构的高度保守, 导致激酶调节剂的选择性差而产生毒副作用, 且几乎所有的蛋白激酶药物在临床使用一段时间后都会面临耐药性的难题, 从2022年批准的小分子激酶调节剂分析发现, 开发具有不同结合模式的抑制剂, 例如共价和变构调节剂, 在新一代激酶药物开发中起到关键性作用: 靶向高度保守的ATP口袋外的变构激酶调节剂通过获得靶点选择性可降低脱靶不良反应, 且在克服耐药性方面也具有一定的优势; 共价抑制剂可通过增加在激酶靶标上的停留时间, 从而提高选择性并降低脱靶效应。此外在之前已批准上市的激酶调节剂中, 80%以上主要用于治疗不同类型的癌症, 治疗领域相对局限, 而2022年共批准了4种激酶调节剂用于治疗除癌症外的其他领域如自身免疫病和炎症疾病等, 这充分表明激酶调节剂应用于多个领域的研究开发是未来的整体趋势。
本文通过浅析上述2022年美国FDA批准的5个小分子激酶调节剂的研发背景、药物设计思路、合成路线以及临床疗效和安全性等, 以期望为更多激酶调节剂的研究提供思路与方法。
1 阿布昔替尼
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1.1 研发背景
AD是一种常见的慢性炎症性皮肤病, 临床表现为剧烈的瘙痒和湿疹性皮损。AD临床发病率较高(15%~20%的儿童和10%的成年人患有不同程度的AD), 且发病因素复杂, 受遗传、免疫以及环境等影响, 其中表皮屏障通透性丧失和免疫失调是AD发病机制中最重要的因素[3]。JAK/STAT信号通路的失调与AD的发病机制相关, 主要表现为表皮趋化因子、促炎细胞因子和血管生成因子的上调, 以及抗菌肽和皮肤屏障功能修复因子的下调[4]。JAK激酶家族由JAK1、JAK2、JAK3 (存在于细胞质) 以及TYK2组成, 不同的细胞因子与JAK激酶结合后, 发生信号传导即受体的激活和二聚化, 进一步导致JAK磷酸化, 从而与STAT结合, 随后STAT磷酸化, 接着STAT二聚体转移到细胞核并正向或负向调节炎症介质的表达[5]。JAK抑制剂可选择性抑制JAK激酶, 从而阻断JAK/STAT通路, 第一代JAK抑制剂以JAK蛋白中的酪氨酸激酶结构域为靶点, 因该结构域高度保守, 导致第一代JAK抑制剂选择性较差, 例如芦可替尼(ruxolitinib)、托法替尼(tofacitinib) 和巴瑞替尼(baricitinib) 等。然而JAK家族介导多种细胞因子的信号传导, 全面抑制会带来多种不良反应, 从而限制其临床应用。第二代JAK抑制剂可以选择性地抑制JAK家族成员, 因此能够实现在抑制特定与疾病相关信号通路的同时, 维持其他细胞因子功能不受影响, 被寄予研发厚望, 例如乌帕替尼(upadacitinib) 和菲卓替尼(fedratinib) 等。由于JAK1在JAK家族成员中具有最广泛的细胞因子信号转导途径, 并且是唯一可以与其他三个JAK激酶配对的亚型, 因此JAK1选择性抑制剂有望抑制与炎症和免疫功能相关的细胞因子。2022年1月15日, 辉瑞公司宣布美国FDA批准其JAK1抑制剂阿布昔替尼上市, 阿布昔替尼是一款选择性抑制JAK1的口服小分子药物, 通过调控参与特异性皮炎病理的多种细胞因子譬如IL-4、IL-13、IL-22和TSLP等而发挥作用, 用于治疗患有复发性中度至重度特应性皮炎的成人患者。
1.2 研发思路
辉瑞公司研究人员首先观察到JAK1/3抑制剂托法替尼(1) 具有较好的激酶选择性, 且该选择性与激酶铰链区结合的吡咯并嘧啶母核相关。因此, 研究人员选择保留吡咯并嘧啶母核, 系统优化托法替尼的3-氨基哌啶基团。结果显示, 带有顺式- 1, 3-环丁烷二胺连接体的磺胺类化合物2对JAK1抑制的IC50为6 nmol·L-1, 且对JAK2具有较好的选择性(IC50 = 0.413 μmol·L-1)。但其清除率较高(HLM = 58 μL·min-1·mg-1), 因此研究人员希望通过对右侧与环丁烷相连的苯基磺酰胺基团进行优化以降低亲脂性(log D), 从而提高代谢稳定性。研究人员主要采用脂肪烷基取代化合物2中苯基, 以及氨基磺酰胺、砜和“反向磺胺”等基团替换磺胺基团, 然而大部分衍生物的活性及选择性均不同程度地下降。因此, 他们选择保留磺胺基团, 对苯基基团进一步优化, 其中带有丙基磺酰胺侧链的化合物PF-04965842 (3) 具有良好的JAK1抑制活性(IC50 = 29 nmol·L-1)、JAK2/JAK1选择性(28倍) 以及体外代谢稳定性(HLM ≤ 9 μL·min-1·mg-1) (图 1A)。化合物3即是上市的阿布昔替尼, 其具有优越的体内口服生物利用度(95.6%) 和在佐剂诱发关节炎小鼠模型(rat adjuvant-induced arthritis, AIA) 中具有较好的抑制活性。通过对比阿布昔替尼与JAK1和JAK2的共晶复合物结构发现, 阿布昔替尼母核上的吡咯N-H和嘧啶N1分别与JAK1和JAK2激酶铰链区上的谷氨酸(Glu957) 和亮氨酸(Leu959) 形成氢键, 侧链上的N-H和磺酰胺基团分别和催化环上天冬酰胺(Asn1008) 的侧链羰基以及精氨酸(Arg1007) 主链的羰基形成氢键。此外, 阿布昔替尼母核上的嘧啶N3与αD-螺旋内谷氨酸(Glu966) 侧链的羧基形成水分子介导的氢键, 而在JAK2中相应的残基是天冬氨酸, 由于距离太远而无法形成水介导的氢键作用, 这种差异解释了阿布昔替尼具有良好的JAK2/JAK1选择性的原因[6] (图 1B)。
1.3 合成路线
辉瑞公司报道的阿布昔替尼商业化合成路线如下: (3-氧代环丁基乙酸酯) 氨基甲酸(3a)与异丙醇反应得到异丙酯中间体3b, 3b在SpRedAm酶催化下经还原胺化反应得到脂类中间体3c; 3c与4-氯-7H-吡咯并[2, 3-d]嘧啶(3d) 发生亲核取代反应得到中间体3e; 接着3e与羟胺盐酸盐发生亲核取代反应得到羟胺中间体3f; 3f在CDI作用下发生Lossen重排得到二胺中间体3g, 研究人员通过单晶结构确认了中间体3g的绝对构型; 最后中间体3g在1-(丙基磺酰基)-1H-1, 2, 4-三唑(3h) 的作用下发生磺酰化反应得到目标产物3 (图 2)。
1.4 临床疗效及安全性
阿布昔替尼已在多项治疗AD的临床试验中得到评估。在首次人体临床I期研究(NCT01835197) 中, 79名健康志愿者接受与阿布昔替尼相关的安全性、耐受性、药代动力学和药效学评估, 研究结果表明阿布昔替尼总体安全且耐受性良好, 无死亡或严重不良反应报告, 较常见的不良反应是头痛(n = 13, 16%)、腹泻(n = 11, 14%) 和恶心(n = 11, 14%)[7]。在评估阿布昔替尼在267名中度至重度AD患者中疗效的临床II期临床试验(NCT02780167) 中, 患者分别接受共12周每天一次10、30、100、200 mg阿布昔替尼或安慰剂治疗。研究结果表明, 200 mg阿布昔替尼组、100 mg阿布昔替尼组和安慰剂组分别有43.8%、29.6%、5.8%的患者在第12周观察到IGA应答(2种剂量阿布昔替尼与安慰剂相比, P < 0.001), 分别有82.6%、59.0%、35.2%的患者在第12周观察到EASI-75 (湿疹面积和严重程度改善超过75%) 应答(2种剂量阿布昔替尼与安慰剂相比, P < 0.001), 且各治疗组瘙痒数值评分与基线检查时相比改善不小于4分的比例分别为22.7%、33.3%、50.0%、63.6%, 安慰剂对照组为25.5%, 其中184例患者(68.9%) 报告了不良反应, 最常见的是AD、上呼吸道感染、头痛、恶心和腹泻[8]。目前有多项旨在评估阿布昔替尼在中度至重度AD患者中的疗效和安全性的III期临床试验已经完结或正在进行, 例如JADE MONO-1和JADE MONO-2这2项研究评估了2种剂量(100和200 mg, 每日一次) 的阿布昔替尼单药疗法与安慰剂相比的疗效和安全性, JADE COMPAR研究评估了2种剂量(100和200 mg, 每日一次) 的阿布昔替尼与安慰剂相比在接受背景局部治疗的患者中的疗效和安全性, 以及JADE DARE研究直接比较在局部治疗基础上200 mg阿布昔替尼与300 mg达必妥在中度至重度特应性皮炎成人患者中的疗效等, 多项III期临床试验证明阿布昔替尼的安全性特征与之前的研究一致, 促进其获批上市[9-11]。
2 帕瑞替尼
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2.1 研发背景
MF是一种由于骨髓造血组织中胶原增生, 其纤维组织严重地影响造血功能所引起的一种骨髓增生性疾病, 临床表现为脾肿大、贫血、血小板减少、骨痛等[12], 目前MF除移植外无其他根治方法, 现有治疗药物均旨在缓解症状, 因此临床急需开发新型治疗药物。JAK2是属于JAK家族中广泛表达的细胞质酪氨酸激酶, 在多种生长因子受体的信号转导中发挥作用。2005年, JAK2 V617F基因突变的发现使人们对MF发病机制的研究取得了突破性进展[12], 约60%的MF患者携带JAK2 V617F基因突变, 该突变通过影响JH2结构域的空间结构而导致JAK2蛋白催化亚基持续活化, 进而引起JAK2-STAT信号转导通路的持续激活, 导致细胞对各种细胞因子敏感性增高而引起增殖和凋亡抑制, 原因如下: ①该突变位于负责调节激酶(JH1) 结构域活性的假激酶(JH2) 结构域; ②结构模型表明617位的缬氨酸和618位的半胱氨酸对于稳定JAK2激酶结构域处于非活性构象是重要的, 当缬氨酸突变为体积较大的苯丙氨酸时会破坏这种抑制相互作用的稳定性, 导致激酶活性增加[13]。芦可替尼和菲卓替尼是首先获批用于治疗MF的JAK2抑制剂, 均通过减弱患者过度活跃的JAK信号以及下游转录激活STAT信号, 进而使脾脏体积减小和症状改善, 但以上两个JAK抑制剂均会出现贫血和血小板减少等血液学不良反应, 且不能根治疾病。此外, 芦可替尼不适用于严重血小板缺乏(血小板计数 < 50×109·L-1) 的患者, 菲卓替尼可能导致严重且致命的韦尼克脑病(Wernicke's encephalopathy, WE), 以上原因导致其临床应用受限[13, 14]。帕瑞替尼是CTI BioPharma公司开发的新一代JAK2/FLT3选择性抑制剂, 于2022年2月28日被美国FDA批准用于治疗伴有严重血小板减少症的骨髓纤维化患者, 其疗效和安全性较芦可替尼和菲卓替尼明显提高, 且适用患者范围更广。
2.2 研发过程
研发早期, 研究人员通过化合物库筛选发现氨基嘧啶类化合物4具有广谱的激酶抑制作用, 并在所测试的细胞株中具有较好的抑制活性。然而基于氨基嘧啶母核的结构已获得大量专利, 开发该类型药物受到一定的限制。受大环天然产物的启发, 研究人员设想, 在保证化合物与激酶铰链区域结合模式不变的基础上, 通过引入linker连接化合物4的两端, 得到结构新颖的大环类化合物。由于直碳链linker具有较高的亲酯性和灵活度可显著增加log P, 且易受到第一阶段代谢的影响, 出于综合考虑, 研究人员引入具有亲水性(包含氧原子) 且不包含可快速代谢基团的烯类linker。首先, 研究人员对linker的类型和长度进行优化, 得到大环化合物5对JAK2和FLT3具有良好的抑制活性(IC50 = 0.070和0.19 μmol·L-1), 但其溶解度较低, 将化合物5对接到JAK2的ATP结合位点, 发现其氨基-嘧啶母核与JAK2蛋白铰链区的亮氨酸(Leu932) 残基形成两个氢键, 大环Linker中的醚氧键与丝氨酸(Ser936) 形成氢键, 且化合物5的甲氧基朝向JAK2蛋白的溶剂前沿区。研究人员在该区域引入亲水性基团以提高溶解度, 采用适当长度的醚链连接吗啉、哌嗪、吡咯等亲水基团取代化合物5中甲氧基, 其中带有吡咯亲水链的化合物6具有适宜的溶解度(solubility > 150 μg·mL-1) 以及良好的JAK2和FLT3抑制活性(IC50 = 0.022和0.023 μmol·L-1)。化合物6吡咯烷的碱性N-H与天冬氨酸(Asp939) 侧链的羧基额外形成氢键相互作用, 这可以解释其对JAK2效力提高的原因。接着研究人员在A环、B环和C环引入小型亲脂基团如甲氧基等进一步占据ATP口袋以提高效力, 得到化合物7对JAK2的抑制活性增强(IC50 = 0.019 μmol·L-1), 对接显示化合物7的甲氧基占据由Gly861、Gly858和Lys882等氨基酸形成的疏水口袋, 但化合物7对FLT3的抑制活性下降(IC50 = 0.15 μmol·L-1) (图 3)。于是研究人员选择化合物6 (帕瑞替尼) 进行后续研究, 其在小鼠体内具有良好的药代动力学特征, 在Ba/F3-JAK2V617F驱动的小鼠骨髓纤维化模型和FLT3-ITD驱动的小鼠白血病模型表现出剂量依赖性的生长抑制作用, 且没有显示明显的不良反应, 因此将其推向临床[15]。
2.3 合成路线
文献[14]报道帕瑞替尼的合成路线如下: 2, 4-二氯嘧啶(6a) 和3-(羟甲基)苯硼酸(6b) 在醋酸钯催化下发生偶联反应得到6c, 6c在碱性条件中与烯丙基溴(6d) 发生取代反应得到烯类中间体6e; 2-羟基-5-硝基苯甲醛(6f) 在碳酸钾存在下与1, 2-氯乙烷(6g) 发生亲核取代反应得到芳香醚化合物6h, 6h的醛基经还原得到伯醇化合物6i, 6i与烯丙基溴(6d) 发生取代反应并在铁/氯化铵条件下硝基被还原得到烯类中间体6j; 接着中间体6e和6j在酸性条件下发生亲核取代反应得到氨基嘧啶类化合物6k, 6k在Grubbs二代催化剂作用下发生烯烃复分解反应关环得到化合物6l, 最后6l和吡咯烷(6m) 发生亲核取代反应得到目标化合物6 (图 4)。
2.4 临床疗效及安全性
帕瑞替尼在I期临床研究中显示出良好的安全性和疗效, 并确定了后续II期研究中的推荐剂量, 即400 mg每日一次[16]。一项在美国和澳大利亚进行的多中心、单臂、开放II期研究(NCT00745550) 评估了帕瑞替尼治疗MF患者的最终疗效和安全性结果, 该研究共纳入40名患者, 治疗持续至第24周时结果显示, 31%的患者通过磁共振成像确定脾脏体积减少不小于35%, 42%的患者通过体格检查确定脾脏大小减少不小于50%。且在除疲劳外的其他症状中, 有50%以上的患者在治疗期间获得了改善。最常见的治疗相关不良事件是1级或2级腹泻(69%) 和恶心(49%)。总体而言, 这项II期多中心研究表明帕瑞替尼可有效减少脾肿大, 并持久改善疾病相关症状, 常见的副作用是可控的[17]。两项临床III期试验进一步评估了帕瑞替尼是否可为基线血细胞减少的MF患者提供治疗选择, 其中III期PERSIST-1试验(NCT01773187) 将帕克替尼400 mg每日一次与最佳可用疗法(best available technology, BAT) (不包括芦可替尼) 对MF患者的治疗效果进行比较, 结果表明无论基线血小板计数如何, 帕克替尼不仅治疗耐受性良好, 且诱导显著和持续的脾脏体积减小和症状减轻[18]; PERSIST-2试验(NCT02055781) 则是评估帕克替尼对血小板基线值小于100×109·L-1的MF患者(先前伴或不伴有抗JAK治疗) 的疗效, 该研究纳入311名患者(其中48%患者既往接受过芦可替尼治疗) 并分为3组(帕克替尼每日一次/两次组和BAT组), 各项指标表明帕克替尼在脾脏体积减小和总症状评分降低两方面的获益, 且每日两次的帕克替尼治疗组达到了主要的脾脏体积减小和总症状评分降低终点, PERSIST-2试验的结果证明帕克替尼对骨髓纤维化和血小板减少症患者的临床益处, 其中包括既往接受过JAK2抑制剂治疗的患者[19]。
3 氘可来昔替尼
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3.1 研发背景
银屑病俗称牛皮癣, 是一种广泛流行的由系统性免疫介导的炎症性皮肤病, 临床表现以红斑、鳞屑为主, 全身均可发病, 以头皮、四肢较为常见[20]。据统计, 全球至少1亿人受此疾病困扰。银屑病的现有治疗方案主要是对症治疗, 但仍有许多中重度银屑病患者未得到充分治疗。因此, 临床急需有效的治疗方法。TYK2作为JAK家族最早被发现的一员, 在人体内广泛表达, 其主要负责调控IL-12、IL-23/IL-17、I型干扰素等细胞因子驱动的促炎、促免疫信号传导和细胞应答, 在银屑病等免疫疾病的发病机制中扮演重要角色。而其他亚型JAK1/2/3则负责调节免疫信号, 参与造血、脂质代谢等多种重要生理功能, 与多种炎性皮肤疾病的发生息息相关, 由此推测仅针对TYK2研究新型的选择性抑制剂, 可以为银屑病提供有效的治疗策略[21-23]。由于JAK家族成员的JH1结构域高度保守, 已上市的JAK抑制剂亚型选择性不高而存在较严重的安全性问题。选择性JAK抑制剂的开发难点在于JAK家族各成员的激酶催化域结构高度保守, 靶向JH2的变构抑制剂可以解决该难题。由于JAK家族4个成员的JH2结构并不相同, 因此通过靶向TYK2的“假激酶”调控域JH2能够选择性地抑制TYK2, 阻断TYK2所支配的IL-23、IL-12和I型干扰素等的信号传导而不抑制其他的JAK通路。百时美施贵宝公司开发的变构抑制剂氘可来昔替尼通过差异化结构设计, 与TYK2的假激酶结构域JH2结合, 使TYK2呈非活性构象。2022年9月9日, 美国FDA批准氘可来昔替尼的上市, 用于治疗适合全身治疗或光疗的中度至重度斑块型银屑病成人。
3.2 研发过程
研究人员通过高通量筛选得到化合物8, 其具有良好的TYK2 JH2抑制活性(IC50 = 0.46 nmol·L-1)、良好的代谢稳定性和高配体效率, 但其选择性差(1 μmol·L-1浓度下对261种激酶中的85种抑制率超过50%)。研究人员通过对C3的酰胺甲基化后得到化合物9, 其激酶选择性显著提高[1 μmol·L-1仅对4类激酶(总共265类) 的抑制率超过50%], 但对TYK2 JH2抑制活性有所下降(IC50 = 1.3 nmol·L-1) (图 5)。共晶结构表明化合物9选择性提高原因在于氨甲基与TYK2蛋白上的丙氨酸(Ala671) 存在疏水相互作用, 而丙氨酸仅存在于9类激酶, 其他激酶在该相应位置一般有体积更大的氨基酸(图 6A)。为进一步提高活性, 研究人员采用甲磺酰基取代C4位的酰胺, 得到化合物10对TYK2 JH2抑制活性略有提高(IC50 = 0.9 nmol·L-1), 共晶结构表明其甲磺酰基与赖氨酸(Lys642) 残基形成额外的氢键, 以及C4位上的N-H和甲酰胺形成分子内氢键而进一步稳定了活性构象(图 6B); 接着为提高分子的代谢稳定性和体内暴露量进一步系统优化得到化合物11, 化合物11的甲基砜上的甲基占据由脯氨酸(Pro694) 以及亮氨酸(Leu741) 侧链所形成的位于C端结构域的亲脂性口袋, 氘代甲酰胺和甲磺酰基与赖氨酸(Lys642) 残基形成相互作用, 且甲磺酰基与C端结构域的精氨酸(Arg738) 以及P环区域的谷氨酰胺(Gln597) 额外形成水分子介导的氢键(图 6C)。当用甲氧基替换甲磺酰基时, 发现其对TYK2 JH2抑制活性减弱(IC50 = 5.2 nmol·L-1), 但具有较好的膜渗透性。为进一步提高活性, 研究人员用杂环“替换结合水”策略得到化合物12 (IC50 = 0.4 nmol·L-1), 其甲基三氮唑与精氨酸(Arg738)侧链的胍基形成新的氢键(图 6D)。但化合物12同时对hERG通道蛋白具有一定的抑制活性(IC50 = 31 μmol·L-1), 存在引起心脏毒性的风险。HERG通道蛋白富含芳香族残基, 通过去除分子多余的芳香环可以减少潜在的π-π相互作用从而降低hERG亲和力。当用环丙酰胺基取代化合物12的氨基嘧啶环时, 得到化合物13。化合物13对hERG的亲和力明显降低(IC50 > 80 μmol·L-1), 验证了设计。然而由于结构中的甲酰胺在体内容易发生去甲基化(去甲基代谢物的激酶选择性会变差), 为提高分子的代谢稳定性, 随后用氘代甲酰胺替换甲酰胺(同位素效应, C-D键更稳定), 使分子半衰期延长和去甲基代谢物比例减少。最后, 研究人员用亲脂性更强、碱性更弱的哒嗪环取代吡啶环, 虽然其碱性更弱, 但由于相邻原子具有孤对电子, 可增加其原子的亲核性而形成更强的氢键, 使得分子在体内暴露量显著提高(Cmax= 7.5 μmol·L-1) 的同时活性基本不变, 最终得到化合物14 (氘可来昔替尼) (图 5)。化合物14具有优良的PK特性, 在银屑病小鼠疾病模型中口服有效且具有剂量依赖性活性, 在结肠炎和狼疮等其他自身免疫性疾病小鼠模型中也表现出显著的活性[24, 25]。
3.3 合成路线
氘可来昔替尼的商业化合成路线如下: 1, 3-丙酮二羧酸二乙酯(14a) 在对乙酰基氨基苯磺酰叠氮化物(Ar-SO2N3)、三丁基膦、醋酸条件下自身关环得到哒嗪类化合物14b; 14b的羟基在三氯氧磷条件下发生氯化反应得到化合物14c; 14c和溴化锂发生亲核取代反应得到中间体14d; 5-氯-2-甲氧基苯腈(14e) 和N-甲基甲酰肼(14f)在碱性条件下自身关环得到化合物14g; 14g经硝化反应得到14h后经催化氢化还原得到中间体14i; 14d和14i在醋酸锌条件下发生亲核取代反应得到化合物14j; 化合物14j和环丙酰胺14k在醋酸钯催化下发生偶联反应得到14l; 最后14l和14m在EDCI作用下发生缩合反应得到目标化合物14 (图 7)。
3.4 临床疗效和安全性
氘可来昔替尼是一种高选择性的TYK2变构抑制剂, 一项随机、双盲、安慰剂对照的临床I期研究(NCT02534636) 旨在评估其在100名健康受试者中的药代动力学、药效学和安全性特征, 在这项首次人体研究中, 氘可来昔替尼以剂量和浓度依赖性方式抑制健康受试者的IL-12/IL-23和I型干扰素通路, 且具有良好的PK和安全性[26]。在一项评估氘可来昔替尼在不同剂量下对中度至重度斑块状银屑病患者的有效性和安全性的临床II期试验(NCT02931838) 中, 67%~75%接受氘可来昔替尼治疗的斑块状银屑病患者在75周时PASI (银屑病面积和严重程度指数) 较基线降低不小于12% (与安慰剂相比, P < 0.001), 而在活动性银屑病关节炎患者中的II期试验中(NCT03881059), 氘可来昔替尼实现了II期试验的主要目标(美国风湿病学会20%改善标准ACR20) 和关键次要目标(包括健康评估问卷-残疾指数HAQ-DI和健康调查简表SF-36评分)[27]。此外, 针对银屑病患者的III期试验(POETYK PSO-1和POETYK PSO-2) 表明氘可来昔替尼对斑块型银屑病患者耐受性良好, 且两个共同主要疗效终点[PASI-75 (银屑病面积与严重性指数减轻75%) 和sPGA0/1 (静态医师总体评估皮肤症状完全清除/几乎完全清除)] 均优于安慰剂和对照药物阿普斯特[28]。基于这些数据, 氘可来昔替尼被美国FDA批准用于治疗适合全身治疗或光疗的中度至重度斑块状银屑病成人患者, 将为免疫介导的疾病提供更方便的替代疗法。
4 福巴替尼
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4.1 研发背景
ICC是一种起源于肝脏的高度侵袭性且致命的原发性上皮癌, 约占肝脏原发性恶性肿瘤的10%~15%。ICC发病率在全球范围内呈上升趋势, 大多数患者被诊断为局部晚期或转移性疾病且预后不良, 针对基因组改变和精准医学结合的策略将为这些患者提供新的治疗途径[29]。成纤维细胞生长因子(fibroblast growth factor, FGF) 家族及其受体包括23种多肽分子(FGF1-23) 和4种酪氨酸激酶跨膜受体(FGFR1-4), 其在肿瘤细胞增殖、存活、迁移和血管生成中发挥重要作用。FGFR融合、重排、易位和基因扩增与多种肿瘤的发生发展密切相关。基因组分析表明, 在13%~50%的ICC患者中鉴定出FGFR2基因融合或重排[30, 31]。在上市的4种FGFR的泛抑制剂中, 培米加替尼(pemigatinib)、英菲格拉替尼(infigratinib) 和福巴替尼(15) 用于晚期ICC化疗耐药后的二线治疗。与早期的多激酶抑制剂相比, FGFR泛抑制剂的安全性有较大提高。福巴替尼是一种不可逆FGFR1-4抑制剂(IC50分别为3.9、1.3、1.6和8.3 nmol·L-1)。福巴替尼和FGFR1的晶体结构显示其与FGFR1激酶结构域P环中的保守半胱氨酸Cys488形成不可逆共价结合[32] (图 8)。福巴替尼能够有效克服可逆抑制剂培米加替尼和英菲格拉替尼的多种继发性耐药突变[33, 34], 但对FGFR2守门残基突变(V565F) 效果较差(IC50 = 83 nmol·L-1)[35]。对接结果显示福巴替尼结构中的二甲氧基苯基与突变后的苯丙氨酸(F565) 会产生空间位阻, 从而影响其结合; 另外, 肿瘤细胞也可能通过关键半胱氨酸残基Cys488的突变获得对不可逆抑制剂福巴替尼的耐药[35]。福巴替尼在体外以几乎相等的亚纳摩尔浓度抑制四种FGFR亚型, 并在多种FGFR基因组突变细胞系和异种移植模型中表现出有效的抗增殖活性, 且多个临床试验表明其在ICC患者中的临床益处。2022年9月30日, 美国FDA加速批准福巴替尼用于既往接受过治疗的、不可切除局部晚期或转移性肝内胆管癌, 伴有FGFR2基因重排(包括基因融合) 的成人患者。然而福巴替尼的具体研发过程暂未报道, 因此本文不做描述。
4.2 合成路线
福巴替尼的合成路线如下: 3-碘-1H-吡唑并[3, 4-d]嘧啶-4-胺(15a) 和3, 5-二甲氧基乙炔苯(15b) 在碘化铜和[1, 1-双(二苯基膦)二茂铁] 二氯化钯二氯甲烷络合物催化下发生偶联反应得到化合物15c; 15c与15d在碳酸钾条件下发生亲核取代反应得到化合物15e; 15e在盐酸存在下脱Boc保护基得到炔类中间体15f; 最后15f与丙烯酰氯15g在碱性条件下发生亲核取代反应得到目标化合物15 (图 9)。
4.3 临床疗效和安全性
福巴替尼是一种不可逆的、高选择性的FGFR1-4抑制剂, 首次人体临床I期剂量递增试验(NCT02052778) 表明福巴替尼在晚期实体瘤患者中具有良好的安全性和药代动力学/药效学特征。一项大型多组织学I期剂量扩展试验对福巴替尼在197例晚期实体瘤患者中的疗效进行了评估, 结果表明福巴替尼的客观有效率(ORR) 为13.7%, 且在FGFR2融合/重排阳性肝内胆管癌中观察到最大的效力(ORR = 25.4%), 一些先前对FGFR抑制剂具有获得性抗性的患者在使用福巴替尼后也得到了缓解, 最常见的不良事件是高磷血症(81.2%)、腹泻(33.5%) 和恶心(30.4%)[36, 37]。福巴替尼的获批主要基于关键的IIb期FOENIX-CCA2研究, 这是一项国际多中心、开放标签、单臂II期临床试验, 该试验共纳入103例FGFR2基因突变(78%为基因重排, 22%为基因融合) 的ICC患者, 患者在入组前接受吉西他滨+铂类化疗(没有接受过其他FGFR抑制剂治疗) 后发生了疾病进展, 在该试验中患者口服福巴替尼(20 mg每天一次) 治疗直到疾病进展或出现不可耐受的不良反应。研究结果显示, 患者的中位随访时间为17.1个月, 中位治疗时间为9.1个月; 103例患者中有43例患者(42%) 获得客观缓解, 其中31例患者获得超过6个月的持续缓解, 中位持续缓解时间为9.7个月; 在103例患者中, 85例患者(83%) 获得疾病控制, 中位无进展生存时间(PFS) 为9.0个月, 中位总生存时间(OS) 为21.7个月。在安全性方面, 福巴替尼的安全性和耐受性良好, 常见的不良事件是高磷血症(85%)、脱发(33%) 和口干(30%), 患者报告的唯一严重不良事件是偏头痛(1.9%)[38]。目前, 福巴替尼正在进行一项随机III期临床研究FOENIX-CCA3试验(NCT04093362), 旨在评估福巴替尼作为FGFR2基因重排晚期或复发性不可切除ICC患者的一线治疗的有效性和安全性。
5 米他匹伐
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5.1 研发背景
PKD是一种罕见的遗传性疾病, 通过累及红细胞糖酵解过程而导致患者出现慢性溶血性贫血, 该疾病能引起一系列严重的并发症, 包括胆结石、肺动脉高压、髓外造血和骨质疏松等, 严重影响患者的生活质量[39]。PK由两个独立的基因(PK-M和PK-LR) 编码, 包括PKM1、PKM2、PKL和PKR四种同工酶, 在人体内以组织特异性的方式表达。其中PKR (红细胞型丙酮酸激酶) 是一种四聚体, 由PK-LR基因编码, 并由内源性激动剂二磷酸果糖(fructose phosphate, FBP) 以变构方式生理性激活, 丙酮酸激酶催化反应是红细胞糖酵解途径中产生ATP的第二个步骤, 在能量生产中发挥重要的作用。PKD诱发慢性溶血性贫血的根源在于PK的功能受到抑制, PK-LR基因突变导致PK活性降低, 从而降低其三磷酸腺苷(ATP) 水平并使上游代谢产物不断累积, 最终使得红细胞寿命缩短并导致慢性溶血[40]。目前, PKD的治疗选择非常有限, 包括输血和脾脏切除, 但两种方法都有一定风险。因此, 通过全新的作用机制实现PK的激活成为潜在的药物设计策略。2012年, Agios Pharmaceuticals公司报道了一类化学结构与作用机制全新的PKR变构激动剂米他匹伐, 其通过结合到PKR四聚体上不同于FBP的变构位点并诱导酶的构象变化以增加其活性来激活野生型或突变型PKR。米他匹伐既不干扰天然配体与活性位点的结合又能够稳定处于突变形式的酶, 通过靶向导致慢性溶血和无效红细胞生成的潜在酶缺陷, 以恢复酶活性[41, 42]。2022年2月17日, 美国FDA批准新药米他匹伐上市, 用于治疗患有PKD, 且出现溶血性贫血的成人患者。
5.2 研发过程
PKM2 (M2型丙酮酸激酶) 是肿瘤细胞有氧糖酵解过程的限速酶, 在多种肿瘤细胞中高表达具有低活性的PKM2 (二聚体), 当通过激动剂将低活性的PKM2二聚体转变为高活性的四聚体后, 有利于抑制糖酵解过程, 从而阻断肿瘤细胞的增殖作用。基于此机制, 2010年, Boxer等[43, 44]通过定量高通量筛选技术从含有300 000个小分子的分子库中获得了两个具有高度特异性且结构各异的PKM2激活剂16和17。机制研究表明化合物16和17作为变构抑制剂可以增强PKM2与其底物磷酸烯醇丙酮酸(PEP) 的亲和力, 但活性有待提高(图 10A)。受此启发, Kung等[45]也通过高通量筛选和结构优化得到一系列PKM2变构激活剂, 并诠释了其生化和细胞表征, 进一步解析了其与PKM2四聚体独特的变构结合模式。首先他们得到具有亚微摩尔活性的新骨架PKM2激动剂18 (AC50 = 0.676 μmol·L-1), 通过对右侧与磺酰胺相连基团的优化, 发现采用非极性平面结构的喹啉环取代苯环时, 得到的化合物19活性有较大幅度的提升(AC50 = 0.017 μmol·L-1), 但其溶解性较差, 难以开展进一步的共晶复合物实验确认其结合模式。当采用亲水性吡嗪环取代原疏水性甲氧基苯环时, 得到化合物20在保持活性的同时水溶性有了大幅提高(AC50 = 0.070 μmol·L-1) (图 10A)。化合物20与PKM2的共晶复合物结构显示其结合在PKM2的变构结构位点, 喹啉环位于由A链的残基Phe26、Leu27和Met30或B链的残基Phe26、Tyr390、Leu394组成的平坦且极性的表面区域, 酰胺上的羰基及磺酰胺上的N-H分别与赖氨酸(Lys311) 和亮氨酸(Leu353) 形成氢键相互作用, 且磺酰胺的两个氧原子分别与酪氨酸(Try390) 主链上的N-H和水分子形成氢键作用(图 10B)。进一步通过基于结构的药物设计与优化得到了成药性质最优的化合物米他匹伐(21, AC50 = 0.062 μmol·L-1), 但具体的优化思路没有详细报道, 对米他匹伐进一步的生物研究表明, 其可作为PKR变构激活剂, 通过结合到PKR四聚体上诱导酶的构象变化以增加其活性来激活野生型或突变型PKR, 在广泛的遗传性溶血性贫血病(包括PKD、α和β-地中海贫血以及镰状细胞病) 中具有安全性和有效性。
5.3 合成路线
米他匹伐的工艺路线(WO2011002817A1/CN102481300B) 如下: 4-氨基苯甲酸乙酯(21a) 在碱性条件下和喹啉基磺酰氯(21b) 发生取代反应得到磺酰胺中间体21c; 21c经碱性水解得到羧酸类化合物21d; 然后21d和N-Boc哌嗪盐酸盐(21e) 在二甲基乙酰胺(DMA) 中发生缩合反应得到酰胺中间体21f; 21f在盐酸条件下脱Boc保护基得到21g; 最后21g和2-环丙基乙醛(21h) 经三乙酰氧基硼氢化钠还原胺化得到目标化合物21 (图 11)。
5.4 临床疗效和安全性
米他匹伐已在多种遗传性溶血性贫血临床试验中进行了评估, 包括PKD、镰状细胞病和地中海贫血等。米他匹伐在成人PKD患者中的临床试验已接近完成, I期临床试验(NCT04000165) 表明米他匹伐具有良好的药代动力学、药效学和安全性特征[46]; II期DRIVE-PK研究(NCT02476916) 评估了米他匹伐在未定期输血的PKD成人患者中的安全性和有效性, 临床数据表明米他匹伐耐受性良好, 最常见的不良反应为轻度头痛、失眠和恶心, 50%的患者血红蛋白(hemoglobin, Hgb) 较基线增加不小于1.0 g·dL-1, 平均最大增加为3.4 g·dL-1, 且注意到潜在基因型与血红蛋白改善之间存在明确关系, 在具有两个非错义突变或两个R479H突变的患者中未见溶血改善和红细胞生成标志物改善[47]; 两项旨在评估米他匹伐在未定期输血或定期输血的PKD成人患者的疗效和安全性的临床III期试验(NCT03548220和NCT03559699) 均达到研究的主要疗效终点(米他匹伐在Hgb改善方面优于安慰剂不小于1.5 g·dL-1和37%的患者实现了不小于33%的输血负担减轻) 和所有次要疗效终点, 进一步推动米他匹伐的获批[48, 49]。除此之外, 米他匹伐还进行α-和β-地中海贫血患者的II期试验和镰状细胞病患者的I期试验评估, 结果表明其在这些更常见的遗传性贫血病中的安全性和有效性, 在这些成功的早期试验之后, 米他匹伐在地中海贫血中的两项III期试验和在镰状细胞病中的II/III期试验正在全球范围内开始进行[50, 51]。
6 结语与展望
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目前已有多种激酶调节剂被批准用于恶性肿瘤、自身免疫病和炎症疾病等的治疗, 激酶靶向药物的发展改变了多种疾病的治疗方式。随着药物的应用, 现有激酶调节剂仍存在一些共性缺陷问题亟待解决。
现已发现人体共有超过500种激酶, 然而已批准上市的激酶调节剂的作用靶标主要集中在EGFR、ABL、CDK、ALK、JAK、FGFR、FLT3等, 不足人体激酶组1/10, 且人体内超过一半已发现的激酶靶点尚未开发有效的分子调节剂, 其在疾病中的功能也存在较大的未知性, 因此, 激酶靶点的开发仍然具有很大的空间。从已批准的上市激酶调节剂来看, 80%以上的适应证主要集中在不同类型的癌症, 治疗领域相对局限。而在2022年共批准了4种激酶调节剂用于治疗除癌症外的其他领域如自身免疫和炎症性疾病等, 临床开发中三分之一的激酶调节剂也涉及肿瘤以外的疾病, 这充分表明随着激酶功能的不断深入了解, 激酶调节剂应用于多个领域的研究开发是未来的整体趋势。
目前获批的激酶药物大多数是通过占据ATP结合位点直接靶向激酶的催化功能, 由于激酶ATP结合口袋氨基酸序列的高度相似性, 导致其对于人类激酶组选择性较差而出现临床阶段的脱靶效应; 此外, 耐药性也是激酶调节剂研发中反复出现的难题, 耐药性分为原发性耐药和获得性耐药, 其中获得性靶向耐药几乎出现在每一个验证的靶点中, 主要原因有以下两个: ①在药物结合的位点发生氨基酸点突变, 导致药物与靶点的结合能力下降, 如较常见的守门残基突变和溶剂前沿突变; ②激活代偿激酶功能的信号通路, 如RAS-RAF-MEK-ERK信号通路等。因此, 开发对理想靶点具有高选择性且脱靶作用小的激酶调节剂是一项艰巨的任务。目前针对激酶药物选择性差和获得性耐药的问题, 许多策略已陆续被开发, 包括: ①针对突变靶标口袋氨基酸残基变化, 设计下一代激酶调节剂; ②使用不同作用机制或结合口袋的小分子调节剂, 如结合于变构口袋的小分子调节剂; ③使用PROTAC、分子胶等小分子降解剂, 通过对靶标的降解, 调节其生理功能; ④针对致病机制复杂, 非单一靶基因驱动的疾病, 开发多靶标激酶调节剂或采取联合用药等。2022年上市的首个TYK2变构抑制剂氘可来昔替尼是打破激酶调节剂传统结合模式的一大成果, 其通过靶向TYK2的假激酶结构域JH2而实现亚型选择性, 为选择性抑制剂的开发提供新的思路, 这也充分表明未来小分子激酶调节剂开发的方向将往更优的治疗指数、安全性、药理特性以及耐药性等发展。
另外, 目前激酶调节剂的开发多是基于先前批准的化合物进一步优化设计的, 因此结构创新性较差, 在药效学以及成药性方面很难有大的突破, 从2022年批准的激酶调节剂的研发过程看, 足够数量、结构各异的化合物库结合高通量筛选等新型技术手段和对新骨架化合物的产生具有重要的推动意义, 另外随着分子生物学和药物AI方面的进步, 将会采取更多种方式来组合开发靶向药物。为继续扩大激酶药物的发现, 目前需要进一步开发和完善高效的化合物筛选和分析技术, 尤其是能够识别新化学物质(包括天然化合物) 的方法。此外, 为加快激酶调节剂的上市, 非临床试验测试模型的升级和更合理的临床试验设计同样至关重要, 只有多学科的共同创新努力, 才能更快地将小分子推向市场, 为患者带来福利。
作者贡献: 郑绚负责文章资料收集与撰写; 陆小云负责文章的选题与修改。
利益冲突: 所有作者无利益冲突。
基金
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  • 国家自然科学基金资助项目(82273763)
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doi: 10.16438/j.0513-4870.2023-0472
  • 接收时间：2023-04-17
  • 首发时间：2025-11-28
  • 出版时间：2024-01-12
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  • 收稿日期：2023-04-17
  • 修回日期：2023-08-21
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国家自然科学基金资助项目(82273763)
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    暨南大学药学院, 广东 广州 510632

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2种不同金属材料的力学参数
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Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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