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【深度报告(gao)】BCR-ABL1变构(gou)抑(yi)制剂,开启靶向治疗新篇章

2021-06-16

变(bian)构调(diao)节(allosteric regulation)在细胞生(sheng)命过(guo)程(cheng)中普(pu)遍存在,包括分子间(jian)非共价相互(hu)作用(yong)、共价修饰(磷酸化、点突变(bian),以(yi)及与小分子的(de)(de)化学反(fan)应(ying)(ying))、细胞环境(jing)(温度、辐射、pH和离子强度)和光吸收(shou)等(deng)[1–4]。变(bian)构效(xiao)应(ying)(ying)精(jing)确控制着细胞的(de)(de)正常生(sheng)命过(guo)程(cheng),包括细胞信号(hao)转导(dao)、代谢、酶的(de)(de)催化以(yi)及基因调(diao)控。蛋白变(bian)构调(diao)节失调(diao)与许(xu)多(duo)疾病密切相关,如癌(ai)症、精(jing)神(shen)障碍(ai)、糖尿病、炎症和免疫疾病等(deng)[5-7]。

变(bian)(bian)(bian)构(gou)(gou)(gou)(gou)药物(wu)是指通过与靶蛋白(bai)上的(de)(de)变(bian)(bian)(bian)构(gou)(gou)(gou)(gou)位(wei)(wei)(wei)点(dian)(dian)(空(kong)间上不同于(yu)常(chang)规活性位(wei)(wei)(wei)点(dian)(dian)或底物(wu)结合位(wei)(wei)(wei)点(dian)(dian)等正构(gou)(gou)(gou)(gou)位(wei)(wei)(wei)点(dian)(dian))相结合,从(cong)而调(diao)控蛋白(bai)生(sheng)物(wu)功能(neng)的(de)(de)效应分子[5,8,9]。这类新型调(diao)节剂可(ke)能(neng)通过两种方式(shi)影响蛋白(bai)的(de)(de)生(sheng)物(wu)效应。一(yi)种是变(bian)(bian)(bian)构(gou)(gou)(gou)(gou)调(diao)节引发变(bian)(bian)(bian)构(gou)(gou)(gou)(gou)位(wei)(wei)(wei)点(dian)(dian)及其邻近原子发生(sheng)扰动(dong)(dong)并重(zhong)新定向,从(cong)而产生(sheng)应变(bian)(bian)(bian)能(neng)并迫使下一(yi)层原子移动(dong)(dong),进而影响下一(yi)层原子。变(bian)(bian)(bian)构(gou)(gou)(gou)(gou)扰动(dong)(dong)通过变(bian)(bian)(bian)构(gou)(gou)(gou)(gou)波形式(shi)从(cong)变(bian)(bian)(bian)构(gou)(gou)(gou)(gou)位(wei)(wei)(wei)点(dian)(dian)传播到正构(gou)(gou)(gou)(gou)位(wei)(wei)(wei)点(dian)(dian),导致正构(gou)(gou)(gou)(gou)位(wei)(wei)(wei)点(dian)(dian)构(gou)(gou)(gou)(gou)象动(dong)(dong)力(li)学(xue)(xue)微调(diao)[1,6,10]。另一(yi)种是最近提出的(de)(de)动(dong)(dong)力(li)学(xue)(xue)驱动(dong)(dong)的(de)(de)变(bian)(bian)(bian)构(gou)(gou)(gou)(gou)概(gai)念,变(bian)(bian)(bian)构(gou)(gou)(gou)(gou)扰动(dong)(dong)遍及整个蛋白(bai)结构(gou)(gou)(gou)(gou)(包括正构(gou)(gou)(gou)(gou)位(wei)(wei)(wei)点(dian)(dian)在内),改变(bian)(bian)(bian)整个蛋白(bai)的(de)(de)振(zhen)动(dong)(dong)模式(shi)和构(gou)(gou)(gou)(gou)象群体,可(ke)引发蛋白(bai)构(gou)(gou)(gou)(gou)象发生(sheng)重(zhong)大变(bian)(bian)(bian)化[11,12]。

一、变构调节剂是研发新风向

相对于(yu)传统的(de)(de)(de)正(zheng)构(gou)(gou)(gou)(gou)(orthosteric)药物(wu),变(bian)构(gou)(gou)(gou)(gou)药物(wu)具有(you)(you)几个显著(zhu)优势:1)克服耐(nai)药性(xing)(xing)(xing):在(zai)抗(kang)(kang)菌、抗(kang)(kang)病毒和抗(kang)(kang)肿瘤治(zhi)疗中(zhong),耐(nai)药性(xing)(xing)(xing)问(wen)题一直是(shi)个难题,变(bian)构(gou)(gou)(gou)(gou)调(diao)(diao)(diao)节剂(ji)(ji)(ji)与正(zheng)构(gou)(gou)(gou)(gou)调(diao)(diao)(diao)节剂(ji)(ji)(ji)作(zuo)用于(yu)靶(ba)(ba)点(dian)(dian)(dian)的(de)(de)(de)不同(tong)位(wei)点(dian)(dian)(dian),基于(yu)不同(tong)的(de)(de)(de)作(zuo)用机制发(fa)挥(hui)药效(xiao),这使变(bian)构(gou)(gou)(gou)(gou)调(diao)(diao)(diao)节剂(ji)(ji)(ji)有(you)(you)可(ke)能(neng)(neng)克服正(zheng)构(gou)(gou)(gou)(gou)调(diao)(diao)(diao)节剂(ji)(ji)(ji)在(zai)治(zhi)疗过程中(zhong)产生的(de)(de)(de)获得性(xing)(xing)(xing)耐(nai)药[13];2)高(gao)(gao)选(xuan)(xuan)择性(xing)(xing)(xing):变(bian)构(gou)(gou)(gou)(gou)位(wei)点(dian)(dian)(dian)的(de)(de)(de)同(tong)源序列较(jiao)低(di),氨基酸(suan)残基保守(shou)性(xing)(xing)(xing)低(di),因此具有(you)(you)更(geng)(geng)高(gao)(gao)的(de)(de)(de)选(xuan)(xuan)择性(xing)(xing)(xing)、更(geng)(geng)低(di)的(de)(de)(de)脱靶(ba)(ba)毒性(xing)(xing)(xing)和更(geng)(geng)低(di)的(de)(de)(de)给药剂(ji)(ji)(ji)量[14];3)解决难成药靶(ba)(ba)点(dian)(dian)(dian)困境:有(you)(you)些(xie)正(zheng)构(gou)(gou)(gou)(gou)位(wei)点(dian)(dian)(dian)口(kou)袋残基高(gao)(gao)度保守(shou),且为极(ji)(ji)性(xing)(xing)(xing)和带电(dian)荷环境,不仅导(dao)致调(diao)(diao)(diao)节剂(ji)(ji)(ji)缺乏选(xuan)(xuan)择性(xing)(xing)(xing)、毒性(xing)(xing)(xing)高(gao)(gao),而且导(dao)致调(diao)(diao)(diao)节剂(ji)(ji)(ji)的(de)(de)(de)细(xi)(xi)胞渗透性(xing)(xing)(xing)和口(kou)服生物(wu)利用度差(cha)而缺乏成药性(xing)(xing)(xing);其次,正(zheng)构(gou)(gou)(gou)(gou)位(wei)点(dian)(dian)(dian)的(de)(de)(de)界面大且平坦(tan),缺少合(he)适的(de)(de)(de)小(xiao)分(fen)子结合(he)口(kou)袋(如蛋(dan)(dan)白相互(hu)作(zuo)用界面类(lei)靶(ba)(ba)点(dian)(dian)(dian));又(you)或者(zhe)天然底物(wu)(ATP/GTP)在(zai)细(xi)(xi)胞中(zhong)的(de)(de)(de)浓(nong)度非(fei)常高(gao)(gao),且与活(huo)性(xing)(xing)(xing)位(wei)点(dian)(dian)(dian)的(de)(de)(de)亲和力非(fei)常强,使得直接靶(ba)(ba)向正(zheng)构(gou)(gou)(gou)(gou)位(wei)点(dian)(dian)(dian)的(de)(de)(de)调(diao)(diao)(diao)节剂(ji)(ji)(ji)极(ji)(ji)难发(fa)挥(hui)作(zuo)用等[15-16];4)变(bian)构(gou)(gou)(gou)(gou)调(diao)(diao)(diao)控可(ke)能(neng)(neng)更(geng)(geng)精准(zhun):有(you)(you)些(xie)蛋(dan)(dan)白功(gong)能(neng)(neng)窗口(kou)较(jiao)小(xiao),既需要调(diao)(diao)(diao)控又(you)不能(neng)(neng)过度调(diao)(diao)(diao)控,而变(bian)构(gou)(gou)(gou)(gou)调(diao)(diao)(diao)节剂(ji)(ji)(ji)可(ke)以(yi)双向调(diao)(diao)(diao)节蛋(dan)(dan)白功(gong)能(neng)(neng),发(fa)挥(hui)精准(zhun)调(diao)(diao)(diao)控作(zuo)用,如变(bian)构(gou)(gou)(gou)(gou)激(ji)动剂(ji)(ji)(ji)更(geng)(geng)不容(rong)易诱导(dao)蛋(dan)(dan)白受到(dao)激(ji)活(huo)作(zuo)用后(hou)脱敏(min)[17]。

由于变(bian)(bian)构(gou)调节药(yao)(yao)(yao)物(wu)显示出巨大(da)的开发前景及其较传统正构(gou)药(yao)(yao)(yao)物(wu)的显著优(you)势,靶(ba)点变(bian)(bian)构(gou)效应已被确立为药(yao)(yao)(yao)物(wu)发现(xian)的新机制,引发了变(bian)(bian)构(gou)药(yao)(yao)(yao)物(wu)发现(xian)、优(you)化以(yi)及临(lin)床开发的热(re)潮,吸引了众多(duo)生物(wu)科技公司和大(da)型(xing)(xing)制药(yao)(yao)(yao)企(qi)业涌入这一热(re)门领域,触发了许多(duo)大(da)额融资(zi)、合作(zuo)与交易[18]。以(yi)下,我(wo)们将以(yi)BCR-ABL1变(bian)(bian)构(gou)抑(yi)制剂为例,全面(mian)介绍这类新型(xing)(xing)药(yao)(yao)(yao)物(wu)的发展历史、作(zuo)用机制、临(lin)床进展、应用潜力等多(duo)方面(mian)内(nei)容。

二、BCR-ABL1抑制剂发展历史

伊马替尼作为首个上市的靶向治疗药物,开创了小分子靶向治疗肿瘤的时代,被美国《时代》周刊誉为”银色子弹“。这款BCR-ABL1抑制剂的成功研发使得原来致死率很高的慢性粒细胞白血病(CML)变成了慢性病,CML的治疗也因此获得了里程碑式的进步[19]。然而,10%~20%的CML患者在接受伊马替尼治疗后产生了获得性耐药,主要原因是BCR-ABL1基因可产生50多种点突变[20]。虽然后续几种二代药物的上市使CML的治疗方案得以革新,为伊马替尼耐药的CML患者带来了更多的临床获益,但是大多数患者仍须持续用药,而且最棘手且最常见的耐药突变BCR-ABL1T315I对目前所有一、二代BCR-ABL1抑制剂均耐药。尽管在国外上市的泊那替尼(Ponatinib)可以克服BCR-ABL1T315I耐药,但该药会引发与治疗相关的动脉血栓形成和肝脏毒性风险,并且体外实验显示,一些少见的单点突变以及多重突变(compound mutations)也会对泊那替尼产生耐药[21]。目前,仍有多家国内外药企在积极开发第三代BCR-ABL1抑制剂,但它们依然是通过与ATP竞争活性位点的正构抑制剂,且结构与泊那替尼相似,因此与泊那替尼类似的安全性以及交叉耐药(cross resistance)问题依然存在。

为克服上述BCR-ABL1T315I以及对泊那替尼单点或多重突变耐药、解决现有药物的不耐受性和毒性问题,制药巨头诺华率先布局了第四代BCR-ABL1变构抑制剂(ABL001),目前该项目正在开展III期临床研究;国内方面,进展最快的是深圳市塔吉瑞生物医药有限公司(以下简称“塔吉瑞”)的TGRX-678,该BCR-ABL1变构抑制剂已经进入临床开发阶段。

三、BCR-ABL1变构抑制剂的作用机制

通常(chang)情况下,ABL1激(ji)酶域(yu)(yu)的变(bian)构(gou)(gou)(gou)(gou)位(wei)点被其(qi)自身N端肉(rou)豆(dou)蔻酰(xian)肽占(zhan)据,诱(you)导SH3-SH2-Kinase结构(gou)(gou)(gou)(gou)域(yu)(yu)发(fa)生交联,可(ke)发(fa)挥负向调(diao)控ABL1激(ji)酶活性的关键(jian)作用,调(diao)控着细(xi)胞正常(chang)增(zeng)殖信号的传(chuan)导(图1)。当BCR与ABL1基因融合后(hou),BCR-ABL1激(ji)酶的N端肉(rou)豆(dou)蔻酰(xian)肽丢失,导致(zhi)ABL1激(ji)酶域(yu)(yu)上的变(bian)构(gou)(gou)(gou)(gou)位(wei)点空缺(que),无(wu)法诱(you)导SH3-SH2-Kinase结构(gou)(gou)(gou)(gou)域(yu)(yu)交联,自抑制平衡被打(da)破,处(chu)于活化(hua)开放构(gou)(gou)(gou)(gou)象,致(zhi)使BCR-ABL1激(ji)酶持续(xu)激(ji)活,诱(you)发(fa)细(xi)胞增(zeng)殖和肿瘤(liu)形(xing)成(图2)[22,23]。

图1. ABL1激酶的N端肉豆蔻酰肽负向调控示意图
图2. BCR-ABL1融合激酶持续激活调控示意图

为(wei)了恢复ABL1激(ji)酶(mei)负向调控功能,诺华和(he)塔吉瑞通(tong)过模拟天然ABL1激(ji)酶(mei)肉豆蔻(kou)酰N端(duan)(duan)肽的(de)功能,分别开发了ABL001 和(he)TGRX-678。这两个分子与激(ji)酶(mei)结(jie)(jie)构(gou)域C端(duan)(duan)肉豆蔻(kou)酰空缺变构(gou)位点(dian)结(jie)(jie)合(图3a紫(zi)色(se)球形区(qu)域),使得(de)SH3和(he)SH2结(jie)(jie)构(gou)域交(jiao)联到激(ji)酶(mei)结(jie)(jie)构(gou)域,将ABL1激(ji)酶(mei)由(you)活(huo)性致癌状(zhuang)态转变为(wei)“封闭”失活(huo)非致癌状(zhuang)态,重(zhong)新稳定了ABL1激(ji)酶(mei)的(de)自(zi)抑(yi)制(zhi)构(gou)象(xiang)(图3),从(cong)而发挥抗(kang)肿瘤(liu)作(zuo)用[24]。

图3.TGRX-678与ABL1激酶别构位点结合诱导SH3、SH2结构域与Kinase结构域交联,使ABL1激酶由活性致癌状态3a转变为失活非致癌状态3b

由此可见(jian),第(di)四代BCR-ABL1抑(yi)制(zhi)剂(ji)的(de)(de)作用(yong)位(wei)点(dian)和(he)(he)机制(zhi)与前三代正(zheng)构(gou)抑(yi)制(zhi)剂(ji)截然不(bu)同(tong)。第(di)一(yi)代抑(yi)制(zhi)剂(ji)伊马替(ti)(ti)尼(ni)(ni)(ni)、第(di)二代抑(yi)制(zhi)剂(ji)达沙替(ti)(ti)尼(ni)(ni)(ni)、尼(ni)(ni)(ni)洛替(ti)(ti)尼(ni)(ni)(ni)、博(bo)苏替(ti)(ti)尼(ni)(ni)(ni)、拉多替(ti)(ti)尼(ni)(ni)(ni)、氟(fu)马替(ti)(ti)尼(ni)(ni)(ni),以及(ji)第(di)三代抑(yi)制(zhi)剂(ji)泊那替(ti)(ti)尼(ni)(ni)(ni)的(de)(de)分子机制(zhi)是(shi)与ATP结(jie)(jie)合位(wei)点(dian)“铰(jiao)链区(qu)”结(jie)(jie)合(图(tu)3a红(hong)色球形区(qu)域(yu)(yu)),为(wei)ATP竞争性(xing)抑(yi)制(zhi)剂(ji),抑(yi)制(zhi)BCR-ABL1激酶(mei)的(de)(de)自身磷酸化和(he)(he)底物磷酸化,从而抑(yi)制(zhi)癌细(xi)胞的(de)(de)增殖和(he)(he)肿瘤(liu)形成(cheng),均为(wei)典型的(de)(de)正(zheng)构(gou)抑(yi)制(zhi)剂(ji)。ABL001和(he)(he)TGRX-678 作用(yong)于BCR-ABL1激酶(mei)域(yu)(yu)的(de)(de)变构(gou)位(wei)点(dian),其位(wei)于ABL1激酶(mei)催(cui)化结(jie)(jie)构(gou)域(yu)(yu)的(de)(de)C端肉豆蔻(kou)酰结(jie)(jie)合位(wei)点(dian)(图(tu)3a紫色球形区(qu)域(yu)(yu)),远离正(zheng)构(gou)ATP活性(xing)位(wei)点(dian)及(ji)T315I突变氨(an)基酸残基,因此ABL001和(he)(he)TGRX-678 与BCR-ABL1结(jie)(jie)合几乎不(bu)受T315I的(de)(de)影响(xiang)。

ABL001和TGRX-678 的变构调节作用不仅能够通过变构“波”的形式引发正构位点构象动力学微调,使得对T315I耐药无效的尼洛替尼重新与BCR-ABL1T315I激酶正构位点结合,恢复其抑制作用。此外,变构抑制剂动力学驱动的变构效应,导致SH3和SH2结构域交联到激酶结构域,使整个蛋白发生重大构象变化,从而形成失活非致癌状态。尽管BCR-ABL1Y253H/T315I多重突变对泊那替尼耐药,但有研究提出泊那替尼与ABL001联用时,泊那替尼可短暂性占据正构活性位点,诱导构象从DFG-in活性构象转变为DFG-out非活性构象,这种构象的改变大大降低了肉豆蔻酰变构位点的柔性,使其能够组装并与ABL001更好的结合。反过来,ABL001与变构位点结合后预计将导致泊那替尼与BCR-ABL1激酶的DFG-out非活性构象进一步持续、稳定的结合,这种”正构-变构“相互协同的调节作用机制,最终导致强有力的激酶抑制,以克服对泊那替尼的突变耐药性[21]。因此,正构抑制剂与变构抑制剂联合可发挥强大的协同作用,产生意想不到的疗效。

四、BCR-ABL抑制剂临床前及临床试验结果

临床(chuang)前研究表明(ming),0.1nM级(ji)别以上的ABL001无论在ATP低浓度(10uM)还(hai)是高浓度(2mM) 条件下,对激酶(mei)的抑(yi)制率相(xiang)当,表明(ming)ABL001是有(you)效的BCR-ABL1非ATP竞争(zheng)性激酶(mei)抑(yi)制剂(ji)。ABL001对BCR-ABL1野生(sheng)型(xing)、T315I及(ji)其它(ta)突变型(xing)的Ba/F3细(xi)胞都有(you)较强(qiang)的生(sheng)物活(huo)性(图4),可有(you)效针(zhen)对正构(gou)抑(yi)制剂(ji)引起的获得耐(nai)药性问题,特别是第一、二(er)代无法克(ke)服的守门残基T315I突变耐(nai)药[24]。

图4. 变构抑制剂与正构抑制剂对BCR-ABL1及其各种突变型的Ba/F3细胞系的活性

此外,多(duo)种(zhong)(zhong)实(shi)验对(dui)ABL001的(de)(de)(de)选(xuan)择(ze)(ze)性进(jin)行了评(ping)估(gu)(gu)。在(zai)ABL001浓度<10uM下,不会抑(yi)(yi)制(zhi)(zhi)(zhi)其它60多(duo)种(zhong)(zhong)重(zhong)组(zu)激酶的(de)(de)(de)磷酸(suan)化(hua)作(zuo)用(yong)[24]。采用(yong)450种(zhong)(zhong)肿(zhong)瘤(liu)(liu)(liu)(liu)细(xi)(xi)胞(bao)(bao),对(dui)ABL001变(bian)构抑(yi)(yi)制(zhi)(zhi)(zhi)剂和(he)正构抑(yi)(yi)制(zhi)(zhi)(zhi)的(de)(de)(de)活(huo)(huo)性和(he)选(xuan)择(ze)(ze)性进(jin)行评(ping)估(gu)(gu)发现,ABL001对(dui)BCR-ABL1阳性肿(zhong)瘤(liu)(liu)(liu)(liu)细(xi)(xi)胞(bao)(bao)表现出(chu)优(you)异的(de)(de)(de)抗增殖活(huo)(huo)性(IC50=1-20nM),而对(dui)BCR-ABL1阴性肿(zhong)瘤(liu)(liu)(liu)(liu)细(xi)(xi)胞(bao)(bao)的(de)(de)(de)抑(yi)(yi)制(zhi)(zhi)(zhi)活(huo)(huo)性较低(di)(IC50>1000nM),并(bing)且(qie)其选(xuan)择(ze)(ze)性优(you)于正构抑(yi)(yi)制(zhi)(zhi)(zhi)剂,如图5所示(shi)。此外,浓度<3uM的(de)(de)(de)ABL001对(dui)G蛋白偶(ou)联(lian)(lian)受体、细(xi)(xi)胞(bao)(bao)转(zhuan)运蛋白、离子通道、核受体和(he)酶无实(shi)质(zhi)性影(ying)响[25]。ABL001不仅克服第一、二代抑(yi)(yi)制(zhi)(zhi)(zhi)剂的(de)(de)(de)耐药性,还(hai)(hai)凸显出(chu)其高度的(de)(de)(de)选(xuan)择(ze)(ze)性,可能避(bi)免出(chu)现第三(san)代抑(yi)(yi)制(zhi)(zhi)(zhi)剂泊(bo)那(nei)替(ti)(ti)尼引起的(de)(de)(de)严重(zhong)毒副作(zuo)用(yong)。临床前研(yan)究还(hai)(hai)表明,ABL001与(yu)尼洛(luo)替(ti)(ti)尼联(lian)(lian)用(yong),这一互补组(zu)合达到了很(hen)强的(de)(de)(de)治(zhi)疗(liao)效果,可完全(quan)控制(zhi)(zhi)(zhi)异种(zhong)(zhong)移植肿(zhong)瘤(liu)(liu)(liu)(liu)小鼠的(de)(de)(de)肿(zhong)瘤(liu)(liu)(liu)(liu)进(jin)展,且(qie)停止(zhi)给药后不易复发(图6)[24]。ABL001与(yu)泊(bo)那(nei)替(ti)(ti)尼联(lian)(lian)用(yong),不仅对(dui)泊(bo)那(nei)替(ti)(ti)尼最强耐药的(de)(de)(de)多(duo)重(zhong)突(tu)(tu)变(bian)Y253H/T315I、E255V/T315I等产生活(huo)(huo)性,还(hai)(hai)能有效抑(yi)(yi)制(zhi)(zhi)(zhi)BCR-ABL1多(duo)重(zhong)突(tu)(tu)变(bian)的(de)(de)(de)出(chu)现并(bing)逆(ni)转(zhuan)泊(bo)那(nei)替(ti)(ti)尼的(de)(de)(de)耐药,系统地解(jie)决(jue)了因(yin)多(duo)重(zhong)突(tu)(tu)变(bian)造成的(de)(de)(de)耐药性问题,且(qie)有望大大降低(di)临床所需泊(bo)那(nei)替(ti)(ti)尼的(de)(de)(de)浓度,减少副作(zuo)用(yong),为CML患(huan)者提供一种(zhong)(zhong)有效的(de)(de)(de)治(zhi)疗(liao)策(ce)略(lve)[21]。

图5. BCR-ABL1抑制剂在BCR-ABL阳性和阴性肿瘤细胞的活性和选择性
图6. ABL001与尼洛替尼联用治疗KCL-22细胞的小鼠移植瘤模型的效果

临床(chuang)(chuang)研(yan)究(jiu)表(biao)明,在(zai)对(dui)既往正(zheng)(zheng)构(gou)(gou)抑制剂(ji)耐(nai)药或发生不可接(jie)(jie)受(shou)的(de)副(fu)作(zuo)用(yong),并且接(jie)(jie)受(shou)过至少两种正(zheng)(zheng)构(gou)(gou)激酶抑制剂(ji)治(zhi)疗(liao)的(de)CML患者(zhe),包括泊那替尼(ni)治(zhi)疗(liao)失败的(de)患者(zhe)和有T315I突变(bian)的(de)患者(zhe)中,ABL001表(biao)现出较好的(de)安全性(xing)和有效(xiao)性(xing)[26]。ABL001与(yu)伊(yi)马替尼(ni)联合(he)应(ying)用(yong)的(de)临床(chuang)(chuang)试验(yan)表(biao)现出有希望的(de)初步疗(liao)效(xiao),且具有良好的(de)安全性(xing)和耐(nai)受(shou)性(xing)[27]。ABL001的(de)一(yi)项III期临床(chuang)(chuang)试验(yan)ASCEMBL结果显示(shi)其与(yu)博苏替尼(ni)(bosutinib)相比,24周的(de)主要分子学缓解(MMR)率显著且更优,研(yan)究(jiu)达到主要终(zhong)点[28]。研(yan)究(jiu)人员正(zheng)(zheng)在(zai)评估ABL001与(yu)其它正(zheng)(zheng)构(gou)(gou)激酶抑制剂(ji)联合(he)用(yong)作(zuo)一(yi)线(xian)CML治(zhi)疗(liao)方(fang)案(an)。ABL001在(zai)治(zhi)疗(liao)CML的(de)临床(chuang)(chuang)试验(yan)中已初显成(cheng)效(xiao),预示(shi)着显著的(de)临床(chuang)(chuang)药用(yong)价(jia)值(zhi)。

TGRX-678是国内首个且研发进展最快的第四代BCR-ABL1变构抑制剂,也是全球第二款BCR-ABL1变构抑制剂,目前已获得中国临床许可(受理号:CXHL2000158/CXHL2000159),正在积极筹备临床试验。临床前体内外研究结果显示,与ABL001相比,TGRX-678对Ba/F3 Bcr-AblT315I细胞的活性和选择性更高,口服生物利用度更佳,动物体内安全性也优于ABL001,有潜力成为best-in-class,因此其在临床上的表现令人期待。

五、总结与展望

基于独特的(de)作(zuo)用(yong)位点和机制,BCR-ABL1变(bian)构(gou)抑(yi)制剂(ji)不(bu)仅(jin)可以用(yong)于治疗(liao)既往对正构(gou)抑(yi)制剂(ji)耐(nai)药(yao)(yao)(yao)(yao)(yao)(包(bao)括守(shou)门残基T315I突变(bian)耐(nai)药(yao)(yao)(yao)(yao)(yao))或不(bu)耐(nai)受的(de)CML患(huan)者,与正构(gou)抑(yi)制剂(ji)的(de)联合(he)应用(yong)还(hai)能(neng)够克(ke)服泊那(nei)替尼单点和多(duo)重耐(nai)药(yao)(yao)(yao)(yao)(yao),降低耐(nai)药(yao)(yao)(yao)(yao)(yao)性(xing)的(de)发生(sheng),逆转药(yao)(yao)(yao)(yao)(yao)物(wu)的(de)获得耐(nai)药(yao)(yao)(yao)(yao)(yao)性(xing),减(jian)少给药(yao)(yao)(yao)(yao)(yao)剂(ji)量,降低毒副作(zuo)用(yong),有(you)望(wang)使患(huan)者长期(qi)维持(chi)无治疗(liao)缓(huan)解,实现功能(neng)性(xing)治愈。BCR-ABL1变(bian)构(gou)抑(yi)制剂(ji)还(hai)有(you)望(wang)用(yong)于治疗(liao)其(qi)(qi)它肿(zhong)瘤或疾病,大幅拓(tuo)展其(qi)(qi)临床适应症和药(yao)(yao)(yao)(yao)(yao)用(yong)价(jia)值。期(qi)待这类新(xin)型药(yao)(yao)(yao)(yao)(yao)物(wu)能(neng)够开启靶(ba)向治疗(liao)的(de)新(xin)篇章,为(wei)更(geng)多(duo)克(ke)服耐(nai)药(yao)(yao)(yao)(yao)(yao)性(xing)药(yao)(yao)(yao)(yao)(yao)物(wu)的(de)研发指引(yin)新(xin)方(fang)向。

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