CN102274230B - Kit突变形式的抑制剂 - Google Patents

Kit突变形式的抑制剂 Download PDF

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CN102274230B
CN102274230B CN201110222445.0A CN201110222445A CN102274230B CN 102274230 B CN102274230 B CN 102274230B CN 201110222445 A CN201110222445 A CN 201110222445A CN 102274230 B CN102274230 B CN 102274230B
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E·布赫东格尔
D·法布罗
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/44—Multiple drug resistance

Abstract

本发明涉及治疗特征为KIT的突变形式的依赖KIT的疾病，其中鉴定了突变KIT并施用了突变KIT的适当抑制剂，所述抑制剂选自米哚妥林、vatalanib和化合物A。

Description

KIT突变形式的抑制剂
本申请是申请日为2004年11月17日、发明名称为“KIT突变形式的抑制剂”的中国专利申请200480033858.2(国际申请号PCT/EP2004/013045)的分案申请。
本发明涉及特征为KIT突变形式的依赖KIT的疾病的治疗，其中鉴定了所述突变KIT和施用了所述突变KIT的适当抑制剂。
c-kit基因编码受体蛋白酪氨酸激酶，其在本文中称作KIT，但也称为肥大/干细胞生长因子受体。KIT的氨基酸序列和c-kit基因的核苷酸序列是已知的。参见Swiss Prot.：P10721。与它的配体干细胞因子结合后，KIT形成二聚体，所述二聚体自磷酸化并活化导致细胞生长的信号级联。导致KIT经活化形式，特别是独立于它的配体的活化的形式的突变是已知的并且认为在某些增生性疾病中起作用，所述疾病为诸如肥大细胞疾病，如肥大细胞增生症，特别是全身性肥大细胞增生症、急性骨髓性白血病、胃肠道间质瘤、sinonasal NK/T-细胞淋巴瘤、精原细胞瘤和无性细胞瘤。
已知作为甲磺酸盐以商品名GLIVEC或GLEEVEC上市的伊马替尼(Imatinib)抑制野生型KIT和某些KIT突变，例如通常在胃肠道间质瘤(GIST)中发现的外显子中的KIT突变。然而，它对某些其它的KIT突变形式，例如通常在全身性肥大细胞增生症中发现的D816V突变也是无活性的或显著较低的活性。本发明基于如下研究：该研究将特征为KIT突变形式的疾病的治疗与适当的备选药物治疗基于该备选药物治疗能够抑制突变KIT而联系起来。
因此，本发明涉及治疗患者中依赖KIT的疾病的方法，所述方法包括
(a)鉴定与依赖KIT的疾病相关的KIT突变形式；和
(b)向所述患者施用有效抑制突变KIT量的抑制剂，所述抑制剂选自米哚妥林(midostaurin)、vatalanib和化合物A。
依赖KIT的疾病一般为增生性疾病，其特征是由于KIT中的活化突变导致的过度KIT激酶活性。此种活化突变是本领域已知的并且通过本领域已知的技术鉴定。
依赖KIT的疾病包括特征为以下已知的KIT突变的疾病：D816F、D816H、D816N、D816Y、D816V、K642E、Y823D、Del550-558、Del557-561、N822K、V654A、N822H、Del550-558+V654A、Del557-561+V654A、Ins503AY、V560G、558NP、Del557-558、DelVV559-560、F522C、Del579、R634W、K642E、T801I、C809G、D820Y、N822K、N822H、Y823D、Y823C和T670I。
在本发明的重要实施方案中，依赖KIT的疾病对伊马替尼的治疗有抗药性。对伊马替尼的治疗有抗药性的依赖KIT的疾病通常为如以上描述的依赖KIT的疾病，其中以400-1000mg/天的剂量施用的伊马替尼不提供对突变KIT的足够抑制以实现显著的治疗益处。一般地，对伊马替尼有抗药性的突变KIT具有突变KIT的体外IC50大于约3微摩尔/升。伊马替尼抗药性KIT突变包括D816F、D816H、D816N、D816Y、D816V、T670I和包括V654A的突变形式。
抑制KIT突变形式的化合物的选择基于检测此种化合物或许多化合物抑制突变KIT的能力。此种检测通过本领域已知的或本领域技术人员技术范围内的标准抑制测定法实施。
根据本发明的方法利用的KIT抑制剂包括米哚妥林、vatalanib和化合物A。米哚妥林(US5；093,330)和vatalanib(WO98/35958)是本领域已知的。化合物A是式
化合物A
的化合物并且可以根据WO04/005281制备。
通过常规方法确定米哚妥林、vatanalib和化合物A的适当剂量。
施用适当剂量的米哚妥林例如，每天一次、两次或三次，每天的总剂量为25-300，优选50-300更优选50-100，最优选100-300mg，例如每天施用两次或三次，每天的总剂量为150-250mg，优选225mg。
Vatanalib的适当的日剂量为300-4000mg，例如300-2000mg/天或300-1500mg/天，特别地，300、500、750、1000、1250、1500或2000mg/天，特别是1250mg/天。
对于70kg/人，化合物A的日剂量为大约0.05-5g，优选大约0.25-1.5g。
图1是含有突变体的质粒图。
实施例
将编码aa544-976的人KIT基因克隆到杆状病毒供体质粒pFB-GST-01。用限制性内切酶Bam H1和EcoR1切割该编码序列并连接到具有相容末端的Bac-to-Bac供体载体pFB-GEX-P1。随后通过本领域技术人员已知的方法将所希望的突变导入到KIT基因中。由于在用于产生突变编码序列的最初质粒中的移码，因此对于如图1显示的每种突变体用限制酶BamH1-EcoR1将突变的质粒插入片段切除并插入到Bac-to-Bac供体载体pFB-GST-01中。自动测序证明每种突变质粒都存在正确的序列。
从用如在材料和方法中描述的pFB-GO1-KIT-突变质粒克隆转化每个DH10Bac细胞的10个菌落产生杆粒DNA，将此种杆粒DNA转染到Sf9细胞中。将转染的细胞沉淀，将培养基上清液中存在的所得重组杆状病毒扩大。使用用于免疫检测的抗KIT和抗GST抗体对经裂解的细胞沉淀物应用蛋白质印迹以证实病毒克隆表达GST-c-KIT融合蛋白。
测定条件：1μMATP，5μg/ml Poly-EY，室温孵育10分钟。
从经转染细胞培养物中收集包含病毒的培养基用于感染以增加它的滴度。两轮感染后获得的包含病毒的培养基用于大规模的蛋白质表达。对于大规模的蛋白质表达，用5x107个细胞/板接种100cm2圆形组织培养板，并用1mL包含病毒的培养基(大约5MOI)感染。3天后，将细胞从培养板刮下，以500转/分钟离心5分钟。来自10-20个100cm2培养板的细胞沉淀物在50mL用冰预冷的裂解缓冲液(25mM Tris-HCI，pH7.5，2mMEDTA，1％NP-40，1mM DTT，1mM PMSF)中重新悬浮。将细胞在冰上搅拌15分钟，然后以5000转/分钟离心20分钟。
将经离心的细胞裂解物加到2mL谷胱甘肽-琼脂糖(sepharose)柱(Pharmacia)上，用10mL的25mM Tris-HCI，pH7.5，2mM EDTA，1mM DTT，200mM NaCI清洗3次。然后通过10次应用(每次1mL)25mM Tris-HCI，pH7.5，10mM还原型谷胱甘肽，100mM NaCI，1mMDTT，10％甘油洗脱GST-标记的蛋白质，-70℃保存。
在存在或不存在抑制剂的20mM Tris-HCI，pH7.6，3mM MnCI2，3mM MgCI2，1mM DTT，10μM Na3VO4，3μg/mL poly(Glu，Tyr)4∶1，1％DMSO，1.5μM ATP(γ-[33P]-ATP 0.1μCi)中测定200-500ng多种Kit突变体的蛋白激酶活性。该测定(30μL)在96孔板中室温进行30分钟，加入20μL的125mM EDTA终止反应。随后，将30μL的反应混合物转移到事先用甲醇浸泡5分钟的Immobilon-PVDF膜(Millipore，Bedford，MA，美国)上，用水清洗，然后用0.5％H3PO4浸泡5分钟，按照到与真空源分离的多头真空装置上。点上所有样品后，连接真空，每个孔用200μL 0.5％H3PO4清洗。将膜除去并在振动器上用1.0％H3PO4清洗4次，用甲醇清洗一次。在室温干燥，固定到Packard Top Count96孔框架并加入10uL/孔的Microscint(Packard)后，对膜进行计数。通过对4种浓度(通常0.01、0.1、1和10μM)一式两份的每种化合物抑制百分率的线性回归分析计算IC50值。蛋白激酶活性的一个单位定义为在室温每mg蛋白质每分钟将1纳摩尔33P从[γ33P]ATP转移到底物蛋白质。

Claims (12)

1.化合物A用于生产治疗患者中依赖KIT的疾病的药物的用途，其中所述依赖KIT的疾病与KIT的突变形式相关并且对伊马替尼的治疗有抗药性，其中所述治疗包括：
(a)鉴定KIT的突变形式，其选自D816F、D816H、D816N、D816Y、D816V、K642E、Y823D、Del 550-558、Del 557-561、N822K、V654A、N822H、Del 550-558+V654A、Del 557-561+V654A、Ins503AY、V560G、558NP、Del 557-558、Del VV559-560、F522C、Del 579、R634W、K642E、T801I、C809G、D820Y、N822K、N822H、Y823D、Y823C和T670I，并且具有突变KIT的体外IC50大于约3微摩尔/升；和
(b)向所述患者施用有效抑制突变KIT量的化合物A，
其中化合物A的结构式如下：
2.根据权利要求1的用途，其中所述KIT的突变形式选自D816F、D816H、D816N、D816Y、D816V、T670I和包括V654A的突变形式。
3.根据权利要求1的用途，其中所述KIT的突变形式选自D816F、D816H、D816N、D816Y、D816V、K642E、Y823D、Del550-558、Del 557-561、N822K、V654A、N822H、Del 550-558+V654A、Del 557-561+V654A。
4.根据权利要求3的用途，其中所述KIT的突变形式为D816N。
5.根据权利要求3的用途，其中所述KIT的突变形式为K642E。
6.根据权利要求3的用途，其中所述KIT的突变形式为Y823D。
7.根据权利要求3的用途，其中所述KIT的突变形式为Del550-558。
8.根据权利要求3的用途，其中所述KIT的突变形式为Del557-561。
9.权利要求3的用途，其中所述KIT的突变形式为N822K。
10.权利要求3的用途，其中所述KIT的突变形式为N822H。
11.根据权利要求2的用途，其中所述KIT的突变形式选自D816H、D816N、K642E、Y823D、Del 550-558、Del 557-561、N822K和N822H。
12.根据权利要求1-11任意一项的用途，其中依赖KIT的疾病选自肥大细胞疾病、急性骨髓性白血病、胃肠道间质瘤、精原细胞瘤和无性细胞瘤。
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