CN110433164A - TGF-beta受体分子抑制剂在治疗小鼠动物模型中急性髓系白血病的应用 - Google Patents
TGF-beta受体分子抑制剂在治疗小鼠动物模型中急性髓系白血病的应用 Download PDFInfo
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Abstract
本发明涉及一种TGF‑beta受体分子抑制剂ly364947在治疗小鼠动物模型中急性髓系白血病(AML)的应用。具体地，本发明提供了TGF‑beta受体‑I型小分子抑制剂ly364947的新用途。该抑制剂可以抑制AML小鼠骨髓中粒‑巨噬细胞祖细胞的体外增殖，有效延长AML骨髓移植嵌合小鼠的生存期，抑制白血病粒细胞在脾脏内的增殖和在肺脏的迁移。本发明为TGF‑beta受体抑制剂在临床上治疗AML提供了一定的实验依据。
Description
技术领域
本发明属于生物技术领域，具体涉及一种TGF-beta受体-I型分子抑制剂在治疗小鼠动物模型中急性髓系白血病的应用。
背景技术
急性髓系白血病(Acute Myeloid Leukemia，AML)是以骨髓与外周血中原始及幼稚髓性细胞异常增生为特征的血液***恶性肿瘤。近年来，随着对AML研究的不断深入及医疗技术的不断提高，AML的治疗效果及预后获得极大改善，但其仍不尽如人意，仅40％～50％的AML患者获得长期生存(Bertoli，S.，et al.，Therapy-related acute myeloidleukemia following treatment of lymphoid malignancies.Oncotarget，2016.)。因此，探寻更安全、高效的AML治疗方法是目前亟待解决的重点及难点问题。现在的综合治疗是以骨髓移植治疗为主，放疗和化疗为辅，并在探讨结合免疫和分子等生物治疗的新方法。
控制正常发育的调控分子经常与恶性肿瘤相关，ras-MAPK激酶通路就是其中最重要的白血病发病机制之一。RAS基因有三个亚型：HRAS，NRAS和KRAS，而KRAS是人造血***恶性疾病最常发生突变的基因之一，且主要发生在髓系和T细胞系恶性疾病中，很少发生于B细胞系(Zhang，J.，et al.，Oncogenic Kras-induced leukemogeneis：hematopoieticstem cells as the initial target and lineage-specific progenitors as thepotential targets for final leukemic transformation.Blood，2009.113：p.1304-1314.)。目前有研究显示20-26％比例的人急性髓系白血病发现具有RAS原癌基因的遗传缺陷(Eisfeld，A.，et al，The mutational oncoprint of recurrent cytogeneticabnormalities in adult patients with de novo acute myeloid leukemia.Leukemia，2017.10：p.2211-2218.)。KRAS基因的12、13密码子的突变导致RAS蛋白的GTP酶活性降低，促使G12D突变蛋白处于与GTP结合的持续激活状态，因而可引起RAS信号的增强，从而导致KRAS蛋白的持续激活，引起细胞增殖分化、恶性转化等改变(Shaw，R.J.and L.C.Cantley，Ras，PI(3)K and mTOR signalling controls tumour cell growth.Nature，2006.441(7092)：p.424-30.Cazzola，M.，M.G Della Porta，and L.Malcovati，The genetic basisof myelodysplasia and its clinical relevance.Blood，2013.122(25)：p.4021-34.)。
Kras基因在白血病中最常见的突变之一为Kras外显子2的由密码子12编码的甘氨酸突变为天冬氨酸，LSL-KrasGl2D小鼠则是在该突变的上游包含有一个两端带有loxp的转录终止密码子，可被Cre重组酶切除，从而导致突变的癌性Kras基因(KrasGl2D/+)的表达(Braun，B.S.，et al.，Somatic activation of oncogenic Kras in hematopoieticcells initiates a rapidly datal myeloproliferative disorder.Proc Natl AcadSci U S A，2004.101(2)：p.597-602.)。Cre转基因小鼠可敲除特异组织中两侧带有Loxp位点的基因序列，而CD2-Cre小鼠中Cre基因的表达由CD2基因控制。CD2基因主要表达于成鼠的造血***中的淋巴干祖细胞，自然杀伤及其前体细胞，所有的浆细胞样和～20％传统树突状细胞，因而CD2-Cre中重组酶主要作用于造血器官的造血细胞，是用来建立造血***特异基因表达或缺失的有效工具(Siegemund，S.，et al.，hCD2-iCre and Vav-iCremediated gene recombination patterns in murine hematopoietic cells.PLoS One，2015.10(4)：p.e0124661.)。
早期的KrasG12D/+转基因和骨髓移植在造血***的研究表明多种表型，包括髓系增生性疾病或T细胞白血病(Chan IT，et al.Conditional expression of oncogenic K-rasfrom its endogenous promoter induces a myeloproliferative disease.J ClinInvest.2004；113(4)：528-538.Kindler，T.，et al.，K-RasG12D-induced T-celllymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive togamma-secretase inhibitors.Blood，2008.112(8)：p.3373-82.)。这些研究大都利用MxCre1诱导成年小鼠的KrasG12D/+癌基因表达。最近，Vav-iCre和Flt3-Cre诱导的KrasG12D/+在胚胎期小鼠表达导致产前致死或发展成围产期髓系粒细胞白血病(Tang，P.，et al.，Differential roles of Kras and Pten in murine leukemogenesis.Leukemia，2013.27(5)：p.1210-4.Tarnawsky，S.P.，et al.，Mice expressing KrasG12D in hematopoieticmultipotent progenitor cells develop neonatal myeloid leukemia.J Clin Invest，2017.127(10)：p.3652-3656.)。本研究已利用LSL-KrasGl2D小鼠和CD2-Cre小鼠建立KrasGl2D/+表达的血液***特异基因突变的小鼠模型，获得KrasGl2D/+稳定一致表达的基因型小鼠，观察其表型为急性髓系白血病。我们在实验中找到其下游靶分子机制，信号通路传导是通过TGF-beta信号通路来调控。因此，针对TGF-beta信号通路或其受体的分子靶向治疗药物是本研究在急性髓系粒细胞白血病药物治疗的探讨重点。
专利号US8298825公开了一类多靶点蛋白激酶抑制剂，它们对TGF-beta受体具有很强的抑制作用。其中，对TGF-beta受体-I型有抑制作用的化合物，如下式(I)所示，其化学名为4-[3-(2-pyridinyl)-1H-pyrazol-4-yl]-quinoline，(4-[3-(2-吡啶基)-1H-吡唑-4-基]-喹啉)。之前研究表明，ly364947可用于体细胞重编程的制备，并应用在慢性腹膜炎小鼠模型，胰腺癌细胞的肿瘤异种移植，和致癌基因BCR-ABL活化的慢性髓系白血病的治疗中(Naka，K.，et al.，TGF-b-FOXO signalling maintains leukaemia-initiating cells inchronic myeloid leukaemia.Nature，2010.463：p.676-680)，暗示ly364947可能用于治疗上述疾病，但未涉及基因遗传背景和病因不明确的急性髓系白血病。
发明内容
本发明的目的是提供一种TGF-beta受体-I型分子抑制剂在小鼠动物模型中治疗急性髓系白血病的应用。本发明提供了一种TGF-beta受体-I型抑制剂的用途，用于制备(i)抑制AML细胞的增殖、和/或(ii)治疗急性髓系白血病的药物组合物。
本发明发现，TGF-beta受体-I型分子抑制剂对于小鼠动物模型的急性髓系粒细胞白血病具有良好的治疗效果。在本发明优选的实施方案中，所述的TGF-beta受体-I型小分子抑制剂为如下的式(I)所示化合物或其可药用盐。本发明中，所述的TGF-beta受体-I型抑制剂的用量可以在1-20mg/kg，优选10mg/kg，所述的用量以化合物(I)的形式计量。
式(I)化合物或其药学上可接受的盐也可以与药学上可接受的载体一起制成本领域熟知的形式，如片剂、胶囊、颗粒剂、注射剂等。本发明涉及含有选自式(I)化合物或者其药学上可接受的盐的化合物在动物模型中制备治疗前述急性髓系白血病的药物中的用途。
附图说明
图1显示化合物(I)处理抑制白血病粒-巨噬祖细胞GMP在M3434培养基体外生长能力。
图2显示化合物(I)单用对小鼠骨髓移植建立急性髓系白血病嵌合鼠生存期的疗效，并使用柔红霉素AraC和阿糖胞苷DNR化疗药治疗作为对照。
图3显示化合物(I)单用对小鼠骨髓移植建立急性髓系白血病嵌合鼠的疗效(肺，肝组织的苏木精-伊红HE染色显示白血病细胞侵润)。箭头表示白血病细胞在肺脏和肝脏中的侵润位点。
图4显示化合物(I)单用影响小鼠骨髓移植建立急性髓系白血病嵌合鼠的骨髓和脾脏中自血病粒-巨噬细胞祖细胞和白血病细胞的计数和流式细胞表型。(A)CD45.1+受体小鼠骨髓和脾脏细胞中供体CD45.2阳性的白血病粒-巨噬祖细胞GMP和髓系白血病粒细胞Mac+Gr1+流式细胞分析。(B)CD45.1+受体小鼠骨髓和脾脏细胞计数。(C)CD45.1+受体小鼠骨髓和脾脏细胞中供体CD45.2阳性的白血病粒-巨噬祖细胞GMP和髓系白血病粒细胞Mac+Gr1+统计图。对照为药物未处理组。
具体实施方式
本发明人首次报道了一种TGF-beta受体-I分子抑制剂ly364947在急性髓系白血病的应用。实验结果表明ly364947即化合物(I)抑制急性髓系白血病小鼠中自血病粒-巨噬祖细胞的增殖，体内实验的结果进一步表明ly364947治疗延长了急性髓系白血病骨髓移植嵌合鼠的生存期，抑制了白血病细胞在脾脏的增殖和肺脏的转移，并显著减少了AML白血病粒-巨噬祖细胞GMP和髓系白血病粒细胞Mac-1+Gr1+在骨髓和脾脏的增殖和分化。这为使用TGF-beta受体-I分子抑制剂在临床上治疗AML提供了一定的实验依据。
以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。
受试药物
受试化合物(I)配置方法：以5mg/mL在DMSO中溶解，并在100μL生理盐水中稀释。
实验动物
表达Kras基因G12D突变蛋白的B6.129S4-Krastm4Tyj/J小鼠，和含有位点特异性CD2启动子的B6.Cg-Tg(CD2-icre)4Kio/J转基因小鼠，购自美国The Jackson Laboratory公司。此两品系小鼠交配繁殖，构成携带有双转基因的子代杂合子小鼠KrasG12D/+；CD2cre+为急性髓系白血病小鼠动物模型。同窝出生的单阳或双阴小鼠仔为对照。CD45.1+表型B6.SJL-CD45.1(Ly5.1)为骨髓移植受体小鼠，购自北京大学医学部动物中心。以上小鼠在天津医科大学动物中心饲养繁殖。饲养环境：SPF级。
免疫细胞表型：粒-巨噬细胞祖细胞(granulocyte-macrophage progenitor，GMP)：Lineage-Sca-1-c-kit+CD16/32h1CD34+，粒细胞(myeloid cells).Mac-1+Gr1+，造血干细胞(KLS)：Lineage-Sca-1+c-kit+。
实验步骤
小鼠集落形成单位检测(Colony-forming-unit assay，CFU Assay)
准备MethoCult 3434(甲基纤维素半固体)培养基，购自STEM CELL公司。流式细胞仪制备对照和KrasG12D/+；CD2Cre+小鼠的骨髓GMP细胞，将合适的细胞量加入分装好的MethoCult 3434半固体培养基中并接种。37℃、含5％CO2、湿度≥95％条件下，培养14天左右，对CFU集落进行检测。
流式细胞检测与分选(Flow cytometry，FACS)
常规方法处理并获取小鼠骨髓或脾脏单个核细胞。对于GMP细胞分析或分选，使用磁珠(CD117 MieroBeads，mouse，购自Mlitenyi Biotec公司)富集c-kit阳性细胞。在细胞表面抗体标记中，GMP细胞分析和分选使用一抗抗体为(Biotin anti-CD4，Biotin anti-CD8，Biotin anti-B220，Biotin anti-Ter119，Biotin anti-Mac1，Biotin-Gr1)，细胞孵育和洗涤重悬后，使用二抗抗体孵育(Lin--APC-Cy7)(Sca1-PE-Cy7)(c-kit-APC)(CD34-FITC)(CD16/32-PE)(CD45.1-PECy5)(CD45.2-PerCy5.5)。髓系粒细胞使用Mac1-PE-Cy7，Gr1-FITC标记。以上抗体购自BD Pharmingen或eBioscience公司。所有数据用BDLSRFortessa或FACSAria III(BD公司)收集，用FlowJo软件(Tree Star，Inc.)分析。
骨髓移植建立AML嵌合鼠
选取32只6-8周受体小鼠(CD45.1+)，致死量辐射照射(9.0Gy)，分两次照射，间隔4h，单次照射剂量为4.5Gy。辐照后小鼠每只尾静脉注射预先准备好的CD45.2+KrasG12D/+；CD2Cre+急性髓系白血病小鼠的骨髓单核细胞悬液，每只注射量为0.2ml(1×106cells)。移植后的小鼠，饲养于SPF级环境，饮用水内加抗生素，每天喂食鸡蛋羹，补充营养，以免小鼠由于辐照导致死亡率升高，每天记录生存状况。移植后10天进行药物处理，分成四组，8只/组：(1)对照组：腹腔注射PBS稀释的DMSO；(2)Ly364947组：腹腔注射10mg·kg-1/2days；(3)阿糖胞苷(Cytarabine，AraC)：腹腔注射50mg·kg-1/days，注射5天；(4)阿糖胞苷/柔红霉素(AraC+DNR)：前五天腹腔注射阿糖胞苷50mg·kg-1/days，第六天开始注射柔红霉素(Daunorubicin，DNR)1mg·kg-1/2days，注射6次。每天记录各组生存期状况。
动物研究由南开大学动物护理和使用委员会批准。所有动物实验均按照美国国立卫生研究院实验动物护理和使用指南(NIH，第8版，2011)进行。经南开大学伦理委员会批准。
数据分析
用GraphPad Prism 6分析数据。组间比较用学生t-检验。P值＜0.05被认为是统计学上显著的。
实施例1
化合物(I)处理抑制白血病粒-巨噬祖细胞GMP在M3434培养基中体外生长的能力。
我们评估抑制TGF-beta信号通路在KrasG12D/+和WT GMP的白血病发生机制。首先，分选GMP细胞使用化合物(I)处理，并在MethoCult 3434(甲基纤维素半固体)培养基中诱导体外增殖和分化(集落形成实验，CFU assay)。结果观察到化合物(I)显著抑制白血病粒-巨噬祖细胞KrasG12D/+GMP的CFU集落形成和的生长能力(图1)。这证明TGF-beta信号通路是KrasG12D重要的下游效应蛋白，化合物(I)治疗影响白血病粒-巨噬祖细胞的体外生长能力。
实施例2
评价化合物(I)，化疗药物柔红霉素AraC和阿糖胞苷DNR对小鼠骨髓移植建立急性髓系白血病嵌合鼠的疗效。
结果发现AraC和AraC/DNR两组小鼠死亡率非常高，而且从给药后第4天就开始死亡，平均生存期为16和17天(图2)。DMSO对照组生存状况接近AraC和AraC/DNR两组小鼠，平均生存期为22天。化合物(I)组存活率最高，其中5只嵌合鼠的生存期延长超过100天(图2)。Log-rank test分析显示P＝0.0109，化合物(I)vs对照组。因此，化合物(I)单用明显抑制小鼠骨髓移植模型中急性髓系粒细胞白血病的发展。这使我们推测，传统的临床治疗方法并不能有效治疗KrasG12D/+基因突变导致的AML，反而会由于化疗药的药性太强导致小鼠过早死亡，而靶向TGF-β信号通路的小分子抑制剂化合物(I)能够有效缓解白血病的发生进程。
实施例3
骨髓移植AML嵌合鼠的肺，肝组织的苏木精-伊红HE染色，显示化合物(I)单用有效抑制AML白血病细胞侵润。箭头表示白血病细胞在肺脏和肝脏中的侵润位点。
我们分析周龄相配的骨髓移植嵌合小鼠各组的组织学检测。化合物(I)显著减少了AML细胞在肝脏和肺脏的侵润和迁移(图3)。因而，TGF-beta受体-I抑制剂化合物(I)有效防止KrasG12D/+白血病的致死率，提示KrasG12D/+；CD2Cre+白血病细胞可能在TGF-beta缺陷的微环境中减弱其恶性癌变能力。
实施例4
化合物(I)单用影响小鼠骨髓移植AML嵌合鼠的骨髓和脾脏中白血病粒-巨噬祖细胞GMP和Mac+Gr1+髓系白血病细胞的计数和流式细胞表型。(A)CD45.1+受体小鼠骨髓和脾脏细胞中供体CD45.2阳性的白血病粒-巨噬祖细胞GMP和髓系白血病粒细胞Mac+Gr1+流式细胞分析。(B)CD45.1+受体小鼠骨髓和脾脏细胞计数。(C)CD45.1+受体小鼠骨髓和脾脏细胞中供体CD45.2阳性的白血病粒-巨噬祖细胞GMP和髓系白血病粒细胞Mac+Gr1+统计图。
针对生存期的状况，我们对化合物(I)组和药物未处理的对照组AML嵌合鼠取骨髓和脾脏进行计数(图4B)，化合物(I)明显减少AML嵌合鼠的骨髓和脾脏细胞数。并且，为了观察其细胞水平的变化，以上嵌合鼠的骨髓和脾脏细胞做了流式细胞检测，也发现化合物(I)组白血病粒-巨噬祖细胞(GMP)以及成熟粒-单核细胞(Mac-1+Gr1+)也有显著减少的趋势(图4A，C)。
结论
化合物(I)单用明显抑制小鼠骨髓移植模型中急性髓系粒细胞白血病的发展，并延长生存期。相比较常规急性髓系粒细胞白血病的化疗药物，柔红霉素和阿糖胞苷，化合物(I)有明显疗效。以上结果提示化合物(I)能有效辅助急性髓系白血病的治疗。
在本发明提及的文献在本申请中引用作为参考。此外应理解，在阅读了本发明的上述内容之后，本领域研发和技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (3)
1.TGF-beta受体分子抑制剂在治疗小鼠动物模型中急性髓系白血病的应用，选择所述TGF-beta受体分子抑制剂是TGF-beta受体-I型小分子抑制剂ly364947。其特征在于，用于制备(i)抑制AML细胞增殖、和/或(ii)治疗急性髓系白血病的药物组合物。
2.根据权利要求1所述的用途，其中所述的TGF-beta受体-I型小分子抑制剂是式(I)所示化合物或其可药用盐，
3.根据权利要求2所述的用途，其中所述的TGF-beta受体-I型小分子抑制剂的用量为1-20mg/kg，优选10mg/kg。
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| WO2021105317A1 (en) * | 2019-11-28 | 2021-06-03 | Origo Biopharma, S.L. | Benzylamide derivatives as inhibitors of transforming growth factor-beta receptor i/alk5 |
| CN115282280A (zh) * | 2022-08-12 | 2022-11-04 | 中国科学技术大学 | TGF-β1信号抑制剂的新用途 |
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| JP2013253065A (ja) * | 2012-06-08 | 2013-12-19 | Kanazawa Univ | 慢性骨髄性白血病治療剤及びそのスクリーニング方法 |
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| JP2013253065A (ja) * | 2012-06-08 | 2013-12-19 | Kanazawa Univ | 慢性骨髄性白血病治療剤及びそのスクリーニング方法 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021105317A1 (en) * | 2019-11-28 | 2021-06-03 | Origo Biopharma, S.L. | Benzylamide derivatives as inhibitors of transforming growth factor-beta receptor i/alk5 |
| CN114787145A (zh) * | 2019-11-28 | 2022-07-22 | 奥里戈生物制药有限公司 | 作为转化生长因子-β受体I/ALK5抑制剂的苯甲酰胺衍生物 |
| CN114787145B (zh) * | 2019-11-28 | 2024-03-26 | 阿戈麦布西班牙股份有限公司 | 作为转化生长因子-β受体I/ALK5抑制剂的苯甲酰胺衍生物 |
| CN115282280A (zh) * | 2022-08-12 | 2022-11-04 | 中国科学技术大学 | TGF-β1信号抑制剂的新用途 |
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