JP2017523141A - がん治療のための組成物及び方法 - Google Patents
がん治療のための組成物及び方法 Download PDFInfo
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- JP2017523141A JP2017523141A JP2016572482A JP2016572482A JP2017523141A JP 2017523141 A JP2017523141 A JP 2017523141A JP 2016572482 A JP2016572482 A JP 2016572482A JP 2016572482 A JP2016572482 A JP 2016572482A JP 2017523141 A JP2017523141 A JP 2017523141A
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Abstract
Description
本出願は、米国特許法第119条(e)の下、2014年6月12日に出願された米国仮出願No.62/011,413に基づく優先権を主張するものであり、その内容全体が参照により本明細書に包含される。
本発明は、米国国立衛生研究所(NIH)認定の助成第AA019996号及び第CA163200号の下、政府の支援を受けて行われた。米国政府は本発明において一定の権利を有する。
本発明は、医学的症状を治療するための、化合物、組成物、方法、及びキットに関する。症状にはがん及び腫瘍が含まれるが、これらに限定されない。
本明細書で引用される全ての刊行物は、個々の刊行物または特許出願がそれぞれ参照により包含されることが具体的かつ個別に指示されているのと同じように、それらの全体が参照により本明細書に包含される。以下の記載には、本発明の理解のために有用であり得る情報が含まれる。これは、本明細書で示されるいずれかの情報が先行技術であることもしくは請求項にかかる本発明に関するものであること、または具体的または暗示的に参照された任意の文献が先行技術であることを認めるものではない。
式中、L1及びL2は、独立してリンカーであり;R1は、それぞれ任意選択的に置換されていてもよい、芳香族部位、アルキル、アシル、シクリル、またはヘテロシクリルであり;R2は、それぞれ任意選択的に置換されていてもよい、水素、低級アルキル、シクリル、ヘテロシクリル、アリール、またはヘテロアリールであり;R3は、存在しないか、または任意選択的に置換されていてもよい芳香族部位であり;pは、0、1、2、3、4、5、6、7、8、9、または10であり;1つのR1−L1−はチアジアゾリジン環の1つの窒素と結合しており、−(CH2)p−R3−L2−C(O)NHOR2はチアジアゾリジン環の他方の窒素と結合している。
式中、L1及びL2は、独立してリンカーであり;R1は、それぞれ任意選択的に置換されていてもよい、芳香族部位、アルキル、アシル、シクリル、またはヘテロシクリルであり;R2は、それぞれ任意選択的に置換されていてもよい、水素、低級アルキル、シクリル、ヘテロシクリル、アリール、またはヘテロアリールであり;R3は、存在しないか、または任意選択的に置換されていてもよい芳香族部位であり;pは、0、1、2、3、4、5、6、7、8、9、または10である。
本明細書で引用される全ての参照文献は、完全に記載されているかのようにその全体が参照により包含される。別段の規定がない限り、本明細書で使用される技術的用語及び科学的用語は、本発明が属する技術分野の当業者によって通常理解されるのと同じ意味を有する。Allen et al.,Remington:The Science and Practice of Pharmacy 22nd ed.,Pharmaceutical Press(2012年9月15日);Hornyak et al.,Introduction to Nanoscience and Nanotechnology,CRC Press(2008);Singleton and Sainsbury,Dictionary of Microbiology and Molecular Biology 3rd ed.,revised ed.,J.Wiley&Sons(New York,NY 2006);Smith,March's Advanced Organic Chemistry Reactions,Mechanisms and Structure 7th ed.,J.Wiley&Sons(New York,NY 2013);Singleton,Dictionary of DNA and Genome Technology 3rd ed.,Wiley−Blackwell(2012年11月28日);及びGreen and Sambrook,Molecular Cloning:A Laboratory Manual 4th ed.,Cold Spring Harbor Laboratory Press(Cold Spring Harbor,NY 2012)は、本出願中で使用される数多くの用語に対する一般的な指針を当業者に与える。抗体の調製方法に関する言及については、Greenfield,Antibodies A Laboratory Manual 2nd ed.,Cold Spring Harbor Press(Cold Spring Harbor NY,2013);Kohler and Milstein,Derivation of specific antibody−producing tissue culture and tumor lines by cell fusion,Eur.J. Immunol.1976 Jul,6(7):511−9;Queen and Selick,Humanized immunoglobulins,米国特許 No.5,585,089(1996年12月);及びRiechmann et al.,Reshaping human antibodies for therapy,Nature 1988年3月24日,332(6162):323−7を参照されたい。
様々な実施形態では、本発明はHDACとGSK3βの両方を阻害する化合物を提供する。HDACとGSK3βの両方を阻害する化合物は、本明細書では二重阻害剤とも呼ばれる。
式中、L1及びL2は、独立してリンカーであり;R1は、それぞれ任意選択的に置換されていてもよい、芳香族部位、アルキル、アシル、シクリル、またはヘテロシクリルであり;R2は、それぞれ任意選択的に置換されていてもよい、水素、アルキル、シクリル、ヘテロシクリル、アリール、またはヘテロアリールであり;R3は、存在しないか、または任意選択的に置換されていてもよい芳香族部位であり;pは、0、1、2、3、4、5、6、7、8、9、10、11、または12であり;1つのR1−L1−はチアジアゾリジン環の1つの窒素と結合しており、−(CH2)p−R3−L2−C(O)NHOR2はチアジアゾリジン環の他方の窒素と結合している。
式中、L1及びL2は、独立してリンカーであり;R1は、それぞれ任意選択的に置換されていてもよい、芳香族部位、アルキル、アシル、シクリル、またはヘテロシクリルであり;R2は、それぞれ任意選択的に置換されていてもよい、水素、低級アルキル、シクリル、ヘテロシクリル、アリール、またはヘテロアリールであり;R3は、存在しないか、または任意選択的に置換されていてもよい芳香族部位であり;pは、0、1、2、3、4、5、6、7、8、9、10、11、または12である。
式中、Xはリンカー(例えばL2)であり、Yは、存在しないかまたは芳香族の置換基である。いくつかの実施形態では、Yは、アルキル、CF3、NO2、CO2H、SO2H、シアノ、ヒドロキシ、チオール、アルキルチオ、アルコキシ、アシル、ハロゲン、アミノ、アルキルアミノ、ジアルキルアミノ、及びこれらの任意の組み合わせからなる群から選択される。Y置換基は1つだけ示されているが、1つより多いY、例えば1つ、2つ、3つ、4つ、または5つのYがベンゼン環上に存在していてもよい。いくつかの実施形態では、Yは存在しない。
式中、Xはリンカー(例えばL2)であり、Yは、存在しないかまたは芳香族の置換基である。いくつかの実施形態では、Yは、アルキル、CF3、NO2、CO2H、SO2H、シアノ、ヒドロキシ、チオール、アルキルチオ、アルコキシ、アシル、ハロゲン、アミノ、アルキルアミノ、ジアルキルアミノ、及びこれらの任意の組み合わせからなる群から選択される。Y置換基は1つだけ示されているが、1つより多いY、例えば1つ、2つ、3つ、4つ、または5つのYがベンゼン環上に存在していてもよい。
式中、Xはリンカー(例えばL2)であり、Yは、存在しないかまたは芳香族の置換基である。いくつかの実施形態では、Yは、アルキル、CF3、NO2、CO2H、SO2H、シアノ、ヒドロキシ、チオール、アルキルチオ、アルコキシ、アシル、ハロゲン、アミノ、アルキルアミノ、ジアルキルアミノ、及びこれらの任意の組み合わせからなる群から選択される。Y置換基は1つだけ示されているが、1つより多いY、例えば1つ、2つ、3つ、4つ、または5つのYがベンゼン環上に存在していてもよい。
様々な実施形態では、本発明は、対象の症状の治療方法、対象の症状の予防方法、対象の発症の可能性の低減方法、対象の症状の重症度の低減方法及び/または対象の症状の進行の鈍化方法を提供する。方法は、以下からなる、あるいは以下から本質的になる、あるいは以下を含む:二重阻害剤の治療有効量を対象に投与する段階であって、それによって対象の症状を治療する、対象の症状を予防する、対象の発症の可能性を低減させる、対象の症状の重症度を低減させる、及び/または対象の症状の進行を鈍化させる、段階。
様々な実施形態では、本発明はHDACとGSK3βの二重阻害剤からなる、またはこれから本質的になる、または含有する、組成物を提供する。本発明に従い、組成物は、対象の症状を治療するために、対象の症状を予防するために、対象の発症の可能性を低減するために、対象の症状の重症度を低減するために、及び/または対象の症状の進行を鈍化させるために、使用することができる。
様々な実施形態では、本発明は、対象の症状を治療するための、対象の症状を予防するための、対象の症状の重症度を低減するための、及び/または対象の症状の進行を鈍化させるための、キットを提供する。キットは、ある量のHDACとGSK3βの二重阻害剤と、対象の症状を治療するための、対象の症状を予防するための、対象の発症の可能性を低減させるための、対象の症状の重症度を低減するための、及び/もしくは対象の症状の進行を鈍化させるための二重阻害剤の使用のための指示書と、からなる、あるいは本質的にこれらからなる、あるいはこれらを含む。
1.式(IV)の化合物:
式中、L1及びL2は、独立してリンカーであり;R1は、それぞれ任意選択的に置換されていてもよい、芳香族部位、アルキル、アシル、シクリル、またはヘテロシクリルであり;R2は、それぞれ任意選択的に置換されていてもよい、水素、低級アルキル、シクリル、ヘテロシクリル、アリール、またはヘテロアリールであり;R3は、存在しないか、または任意選択的に置換されていてもよい芳香族部位であり;pは、0、1、2、3、4、5、6、7、8、9、または10であり;−L1R1はチアジアゾリジン環の1つの窒素と結合しており、−(CH2)p−R3−L2−C(O)NHOR2はチアジアゾリジン環の他方の窒素と結合している。
2.式(VI)の構造を有する第1項の化合物:
。
3.式(I)の構造を有する第1項または第2項に記載の化合物:
式中、Xはリンカーであり、Yは、存在しないかまたは芳香族の置換基である。
4.式(I−1)の構造を有する第1項〜第3項のいずれか1項に記載の化合物:
式中、nは1〜12の整数である。
5.以下:
である、第1項〜第4項のいずれか1項に記載の化合物。
6.式(VI)の構造を有する第2項に記載の化合物:
。
7.式(II)の構造を有する第1項、第2項、または第6項のいずれか1項に記載の化合物:
式中、Xはリンカー基であり、Rは−L1R1である。
8.式(II−1)の構造を有する第1項、第2項、第6項、または第7項のいずれか1項に記載の化合物:
。
9.式(V)の化合物:
式中、L1及びL2は、独立してリンカーであり;R1は、それぞれ任意選択的に置換されていてもよい、芳香族部位、アルキル、アシル、シクリル、またはヘテロシクリルであり;R2は、それぞれ任意選択的に置換されていてもよい、水素、低級アルキル、シクリル、ヘテロシクリル、アリール、またはヘテロアリールであり;R3は、存在しないか、または任意選択的に置換されていてもよい芳香族部位であり;pは、0、1、2、3、4、5、6、7、8、9、または10である。
10.式(III)の構造を有する第9項に記載の化合物:
式中、Xはリンカー基であり、Yは、存在しないかまたは芳香族の置換基である。
11.式(III−1)の構造を有する第9項または第10項に記載の化合物:
。
12.式(IIIb)の構造を有する第9項に記載の化合物:
式中、Xはリンカー基であり、Yは、存在しないかまたは芳香族の置換基である。
13.式(IIIb−1)のものである、第9項または第12項に記載の化合物:
。
14.粒子と結合している、第1項〜第13項のいずれか1項に記載の化合物。
15.前記粒子が磁性粒子である、第14項に記載の化合物。
16.開裂可能な連結基を含むリンカーを介して粒子と結合している、第14項または第15項に記載の化合物。
17.前記開裂可能な連結基が酵素によって切断される、第16項に記載の化合物。
18.前記開裂可能な連結基が、がんまたは腫瘍中に多く存在する酵素によって切断される、第16項または第17項に記載の化合物。
19.前記開裂可能な連結基が、がんまたは腫瘍中に多く存在するペプチダーゼによって切断される、第16項〜第18項のいずれか1項に記載の化合物。
20.前記開裂可能な連結基が、カテプシンGの開裂可能な基質である、第16項〜第19項のいずれか1項に記載の化合物。
21.HDACとGSK3βの二重阻害剤を含有する組成物。
22.前記二重阻害剤が第1項〜第20項のいずれか1項に記載の化合物である、第21項に記載の組成物。
23.薬学的に許容可能な担体または賦形剤を更に含有する、第21項または第22項に記載の組成物。
24.局所投与用に、血管内投与用に、静脈内投与用に、動脈内投与用に、腫瘍内投与用に、筋肉内投与用に、皮下投与用に、腹腔内投与用に、鼻腔内投与用に、または経口投与用に製剤される、第21項〜第23項のいずれか1項に記載の組成物。
25.抗がん治療剤を更に含有する、第21項〜第24項のいずれか1項に記載の組成物。
26.前記抗がん治療剤が化学療法剤である、第25項に記載の組成物。
27.以下の段階を含む、対象の症状の治療方法、対象の症状の予防方法、対象の発症の可能性の低減方法、対象の症状の重症度の低減方法、及び/または対象の症状の進行の鈍化方法:
HDACとGSK3βの二重阻害剤の治療有効量を対象に投与する段階であって、それによって対象の症状を治療する、対象の症状を予防する、対象の発症の可能性を低減させる、対象の症状の重症度を低減させる、及び/または対象の症状の進行を鈍化させる、段階。
28.前記症状が、がんまたは腫瘍である、第27項に記載の方法。
29.前記症状が、膵がんである、第27項または第28項に記載の方法。
30.前記対象がヒトである、第27項〜第29項のいずれか1項に記載の方法。
31.前記二重阻害剤が第1項〜第20項のいずれか1項に記載の化合物である、第27項〜第30項のいずれか1項に記載の方法。
32.前記二重阻害剤が局所的に、血管内に、静脈内に、動脈内に、腫瘍内に、筋肉内に、皮下に、腹腔内に、鼻腔内に、または経口的に投与される、第27項〜第32項のいずれか1項に記載の方法。
33.前記二重阻害剤が、約0.001〜0.01、0.01〜0.1、0.1〜0.5、0.5〜5、5〜10、10〜20、20〜50、50〜100、100〜200、200〜300、300〜400、400〜500、500〜600、600〜700、700〜800、800〜900、もしくは900〜1000mg/kg、またはこれらの組み合わせで投与される、第27項〜第32項のいずれか1項に記載の方法。
34.前記二重阻害剤が、約0.001〜0.01、0.01〜0.1、0.1〜0.5、0.5〜5、5〜10、10〜20、20〜50、50〜100、100〜200、200〜300、300〜400、400〜500、500〜600、600〜700、700〜800、800〜900、もしくは900〜1000μg/kg、またはこれらの組み合わせで投与される、第27項〜第32項のいずれか1項に記載の方法。
35.前記二重阻害剤が、およそ、1日に1〜3回、1週間に1〜7回、または1か月に1〜9回投与される、第27項〜34項のいずれか1項に記載の方法。
36.前記二重阻害剤が、約1〜10日間、10〜20日間、20〜30日間、30〜40日間、40〜50日間、50〜60日間、60〜70日間、70〜80日間、80〜90日間、90〜100日間、1〜6か月間、6〜12か月間、または1〜5年間投与される、第27項〜35項のいずれか1項に記載の方法。
37.追加的な抗がん療法を行う段階を更に含む、第27項〜第3627項のいずれか1項に記載の方法。
38.前記二重阻害剤と前記追加的な抗がん療法が、同時にまたは逐次的に施される、第37項に記載の方法。
39.前記追加的な抗がん療法が施される前、施されている最中、または施された後に、前記二重阻害剤が投与される、第37項または第38項に記載の方法。
40.前記追加的な抗がん療法が、外科手術、放射線療法(放射線治療)、生物学的療法、免疫療法、化学療法、及びこれらの任意の組み合わせからなる群から選択される、第37項〜第39項のいずれか1項に記載の方法。
41.前記追加的な抗がん療法が、前記対象に抗がん治療剤を投与することを含む、第37項〜第40項のいずれか1項に記載の方法。
42.前記二重阻害剤と前記抗がん治療剤が、1つの組成物中で提供される、第41項に記載の方法。
43.前記二重阻害剤と前記抗がん治療剤が、別個の組成物中で提供される、第41項または第42項に記載の方法。
44.前記抗がん治療剤が化学療法剤である、第41項〜第43項のいずれか1項に記載の方法。
45.前記二重阻害剤が磁性粒子と結合しており、前記方法が、磁場を使用して二重阻害剤をがんまたは腫瘍へと導く段階を更に含む、第27項〜第44項のいずれか1項に記載の方法。
46.HDACとGSK3βの二重阻害剤;及び
対象の症状を治療するための、対象の症状を予防するための、対象の発症の可能性を低減させるための、対象の症状の重症度を低減するための、及び/または対象の症状の進行を鈍化させるための、前記二重阻害剤の使用のための指示書
を含む、対象の症状を治療するための、対象の症状を予防するための、対象の発症の可能性を低減させるための、対象の症状の重症度を低減するための、及び/または対象の症状の進行を鈍化させるための、キット。
47.前記HDACとGSK3βの二重阻害剤が、第1項〜第20項のいずれか1項に記載の化合物である、第46項に記載のキット。
48.抗がん治療剤を更に含む、第46項または第47項に記載のキット。
49.前記抗がん治療剤が化学療法剤である。第48項に記載のキット。
50.HDAC阻害剤とGSK3β阻害剤とを含有する組成物。
51.前記HDAC阻害剤が、SAHA、TSA、TPX、MS−275、バルプロ酸、もしくはCHAP31、またはこれらの機能的な等価体、類似体、誘導体もしくは塩、及びこれらの任意の組み合わせからなる群から選択される、第50項に記載の組成物。
52.前記GSK3β阻害剤が、SB216763、TDZD−8、チデグルシブ(NP−12)、またはこれらの機能的な等価体、類似体、誘導体もしくは塩、及びこれらの任意の組み合わせからなる群から選択される、第50項または第51項に記載の組成物。
53.前記HDAC阻害剤及び/または前記GSK3β阻害剤が、約0.001〜0.01、0.01〜0.1、0.1〜0.5、0.5〜5、5〜10、10〜20、20〜50、50〜100、100〜200、200〜300、300〜400、400〜500、500〜600、600〜700、700〜800、800〜900、もしくは900〜1000mg/kg、またはこれらの組み合わせである、第50項〜第52項のいずれか1項に記載の組成物。
54.前記HDAC阻害剤及び/または前記GSK3β阻害剤が、約0.001〜0.01、0.01〜0.1、0.1〜0.5、0.5〜5、5〜10、10〜20、20〜50、50〜100、100〜200、200〜300、300〜400、400〜500、500〜600、600〜700、700〜800、800〜900、もしくは900〜1000μg/kg、またはこれらの組み合わせである、第50項〜第53項のいずれか1項に記載の組成物。
55.薬学的に許容可能な賦形剤または担体を更に含有する、第50項〜第54項のいずれか1項に記載の組成物。
56.前局所投与用に、脈管内投与用に、静脈内投与用に、動脈内投与用に、腫瘍内投与用に、筋肉内投与用に、皮下投与用に、腹腔内投与用に、鼻腔内投与用に、または経口投与用に製剤される、第50項〜第55項のいずれか1項に記載の組成物。
57.抗がん治療剤を更に含有する、第50項〜第56項のいずれか1項に記載の組成物。
58.前記抗がん治療剤が化学療法剤である、第57項に記載の組成物。
59.前記HDAC阻害剤と前記GSK3βのうちの少なくとも1つが粒子と結合している、第57項または第58項に記載の組成物。
60.前記粒子が磁性粒子である、第59項に記載の組成物。
61.前記HDAC阻害剤及び/または前記GSK3βが、開裂可能な連結基を含むリンカーを介して前記粒子と結合している、第59項または第60項に記載の組成物。
62.前記開裂可能な連結基が酵素によって切断される、第61項に記載の組成物。
63.前記開裂可能な連結基が、がんまたは腫瘍中に多く存在する酵素によって切断される、第61項または第62項に記載の組成物。
64.前記開裂可能な連結基が、がんまたは腫瘍中に多く存在するペプチダーゼによって切断される、第61項〜第63項のいずれか1項に記載の組成物。
65.前記開裂可能な連結基が、カテプシンGの開裂可能な基質である、第61項〜第64項のいずれか1項に記載の組成物。
66.以下の段階を含む、対象の症状の治療方法、対象の症状の予防方法、対象の発症の可能性の低減方法、対象の症状の重症度の低減方法、及び/または対象の症状の進行の鈍化方法:
HDAC阻害剤及びGSK3β阻害剤の治療有効量を対象に投与する段階であって、それによって対象の症状を治療する、対象の症状を予防する、対象の発症の可能性を低減させる、対象の症状の重症度を低減させる、及び/または対象の症状の進行を鈍化させる、段階。
67.前記症状が、がんまたは腫瘍である、第66項に記載の方法。
68.前記症状が、膵がんである、第66項または第67項に記載の方法。
69.前記対象がヒトである、第66項〜第68項のいずれか1項に記載の方法。
70.前記HDAC阻害剤と前記GSK3β阻害剤が、1つの組成物中で提供される、第66項〜第69項のいずれか1項に記載の方法。
71.前記HDAC阻害剤と前記GSK3β阻害剤が、別個の組成物中で提供される、第66項〜第69項のいずれか1項に記載の方法。
72.前記HDAC阻害剤と前記GSK3β阻害剤が同時にまたは逐次的に投与される、第66項〜第71項のいずれか1項記載の方法。
73.前記GSK3β阻害剤の投与前、投与中、または投与後に、前記HDAC阻害剤が投与される、第66項〜第72項のいずれか1項に記載の方法。
74.前記HDAC阻害剤が、SAHA、TSA、TPX、MS−275、バルプロ酸、もしくはCHAP31、またはこれらの機能的な等価体、類似体、誘導体もしくは塩、またはこれらの組み合わせである、第66項〜第73項のいずれか1項に記載の方法。
75.前記GSK3β阻害剤が、SB216763、TDZD−8、もしくはチデグルシブ(NP−12)、またはこれらの機能的な等価体、類似体、誘導体もしくは塩、またはこれらの組み合わせである、第66項〜第74項のいずれか1項に記載の方法。
76.前記HDAC阻害剤及び/または前記GSK3β阻害剤が、局所的に、脈管内に、静脈内に、動脈内に、腫瘍内に、筋肉内に、皮下に、腹腔内に、鼻腔内に、または経口的に投与される、第66項〜第75項のいずれか1項に記載の方法。
77.前記HDAC阻害剤及び/または前記GSK3β阻害剤が、約0.001〜0.01、0.01〜0.1、0.1〜0.5、0.5〜5、5〜10、10〜20、20〜50、50〜100、100〜200、200〜300、300〜400、400〜500、500〜600、600〜700、700〜800、800〜900、もしくは900〜1000mg/kg、またはこれらの組み合わせで投与される、第66項〜第76項のいずれか1項に記載の方法。
78.前記HDAC阻害剤及び/または前記GSK3β阻害剤が、約0.001〜0.01、0.01〜0.1、0.1〜0.5、0.5〜5、5〜10、10〜20、20〜50、50〜100、100〜200、200〜300、300〜400、400〜500、500〜600、600〜700、700〜800、800〜900、もしくは900〜1000μg/kg、またはこれらの組み合わせで投与される、第66項〜第76項のいずれか1項に記載の方法。
79.前記HDAC阻害剤及び/または前記GSK3β阻害剤が、およそ、1日に1〜3回、1週間に1〜7回、または1か月に1〜9回投与される、第66項〜第78項のいずれか1項に記載の方法。
80.前記HDAC阻害剤及び/または前記GSK3β阻害剤が、約1〜10日間、10〜20日間、20〜30日間、30〜40日間、40〜50日間、50〜60日間、60〜70日間、70〜80日間、80〜90日間、90〜100日間、1〜6か月間、6〜12か月間、または1〜5年間投与される、第66項〜第79項のいずれか1項に記載の方法。
81.追加的な抗がん療法を行うことを更に含む、第66項〜第8027項のいずれか1項に記載の方法。
82.前記HDAC阻害剤、前記GSK3β阻害剤、及び前記追加的な抗がん療法が、同時にまたは逐次的に施される、第81項に記載の方法。
83.前記追加的な抗がん療法が施される前、施されている最中、または施された後に、前記HDAC阻害剤及び/または前記GSK3β阻害剤が投与される、第81項または第82項に記載の方法。
84.前記追加的な抗がん療法が、外科手術、放射線療法(放射線治療)、生物学的療法、免疫療法、化学療法、及びこれらの任意の組み合わせからなる群から選択される、第81項〜第83項のいずれか1項に記載の方法。
85.前記追加的な抗がん療法が、前記対象に抗がん治療剤を投与することを含む、第81項〜第84項のいずれか1項に記載の方法。
86.前記HDAC阻害剤、前記GSK3β阻害剤、及び前記化学療法剤が、別個の組成物中で提供される、第81項〜第85項のいずれか1項に記載の方法。
87.前記HDAC阻害剤、前記GSK3β阻害剤、及び前記抗がん治療剤のうちの少なくとも2つが、1つの組成物中で提供される、第81項〜第85項のいずれか1項に記載の方法。
88.前記HDAC阻害剤、前記GSK3β阻害剤、及び前記抗がん治療剤の3つ全てが1つの組成物中で提供される、第81項〜第85項のいずれか1項に記載の方法。
89.前記抗がん治療剤が化学療法剤である、第81項〜第88項のいずれか1項に記載の方法。
90.前記HDAC阻害剤と前記GSK3βのうちの少なくとも1つが粒子と結合している、第66項に記載の方法。
91.前記粒子が磁性粒子である、第90項に記載の方法。
92.前記HDAC阻害剤及び/または前記GSK3βが、開裂可能な連結基を含むリンカーを介して前記粒子と結合している、第90項または第91項に記載の方法。
93.前記開裂可能な連結基が酵素によって切断される、第92項に記載の方法。
94.前記開裂可能な連結基が、がんまたは腫瘍中に多く存在する酵素によって切断される、第92項または第93項に記載の方法。
95.前記開裂可能な連結基が、がんまたは腫瘍中に多く存在するペプチダーゼによって切断される、第92項〜第94項のいずれか1項に記載の方法。
96.前記開裂可能な連結基が、カテプシンGの開裂可能な基質である、第92項〜第95項いずれか1項に記載の方法。
97.前記HDAC阻害剤と前記GSK3βのうちの少なくとも1つが磁性粒子と結合しており、前記方法が、磁場を使用して前記HDAC阻害剤及び/または前記GSK3βをがんまたは腫瘍へと導く段階を更に含む、第92項〜第96項のいずれか1項に記載の方法。
98.HDAC阻害剤;
GSK3β阻害剤;及び
対象の症状を治療するための、対象の症状を予防するための、対象の発症の可能性を低減させるための、対象の症状の重症度を低減するための、及び/または対象の症状の進行を鈍化させるための、前記HDAC阻害剤及び前記GSK3β阻害剤の使用のための指示書
を含む、対象の症状を治療するための、対象の症状を予防するための、対象の発症の可能性を低減させるための、対象の症状の重症度を低減するための、及び/または対象の症状の進行を鈍化させるための、キット。
99.抗がん治療剤を更に含む、第98項に記載のキット。
100.前記抗がん治療剤が化学療法剤である、第98項または第99項に記載のキット。
101.前記HDAC阻害剤と前記GSK3βのうちの少なくとも1つが粒子と結合している、第98項〜第101項のいずれか1項に記載のキット。
102.前記粒子が磁性粒子である、第101項に記載のキット。
103.前記HDAC阻害剤及び/または前記GSK3βが、開裂可能な連結基を含むリンカーを介して前記粒子と結合している、第101項または102項に記載のキット。
104.前記開裂可能な連結基が酵素によって切断される、第103項に記載のキット。
105.前記開裂可能な連結基が、がんまたは腫瘍中に多く存在する酵素によって切断される、第103項または第104項に記載のキット。
106.前記開裂可能な連結基が、がんまたは腫瘍中に多く存在するペプチダーゼによって切断される、第103項〜第105項のいずれか1項に記載のキット。
107.前記開裂可能な連結基が、カテプシンGの開裂可能な基質である、第103項〜第106項のいずれか1項に記載のキット。
新規な化合物、並びに、成長促進GSKβ、転移、及び治療抵抗性促進HDACを同時に阻害する方法による膵がんの治療
様々な実施形態において、本発明は、κ−rasによる新生物のための、GSK3βとHDACの両方の阻害剤を組み合わせたがん治療を提供する。一般的なスキームは図1に示されており、実験結果は図2〜7に示されている。
細胞生存率に対するALB−185357の影響
様々な用量のsahaとチデグルシブの組み合わせの存在下もしくは不存在下、またはALB−185357と共に、BxPC−3膵がん細胞株を72の間培養し、MTTアッセイによって細胞生存率を測定した。図13中のデータは、化合物ALB−185357が用量に依存して細胞生存率を減少させたことを示している。ALB−185357の作用の効果は、HDAC阻害剤のsahaとGSK−3β阻害剤のチデグルシブの組み合わせよりも大きい。300nMのALB−185357を使用した場合に有意性が得られ、また細胞生存率に対するその効果はsahaとチデグルシブの組み合わせの効果よりも大きかった。図4及び図7から分かるように、sahaとチデグルシブの組み合わせは細胞死、増殖、及びEMTの測定に対して相乗効果を有していた。したがって、ALB−185357の効果(HDACとGSK3βの二重阻害剤)は、個々の薬剤の組み合わせで観察された相乗効果に対する追加的な相乗効果を示す。
様々な用量のALB−185357の存在下もしくは不存在下、MIA PaCa−2細胞を72の間培養し、DNA断片化を測定することによってアポトーシスを評価した。結果は図14に示されている。図14中のデータから分かるように、DNA断片化レベルにより測定したアポトーシスをALB−185357が用量に依存して増加させ、有意差は300nMの用量で得られた。
様々な用量のALB−185357または1ng/mlの低用量のゲムシタビンの存在下もしくは不存在下、MIA PaCa−2細胞を72の間培養し、DNA断片化を測定することによってアポトーシスを評価した。図15中のデータは、ALB−185357とゲムシタビンの組み合わせが、それぞれの薬剤単独と比較して、または見込まれる追加的な効果と比較して、アポトーシス誘導に対してより大きな効果を生じさせることを示している。
様々な用量のALB−188540またはALB−185643の存在下もしくは不存在下、BxPC−3膵がん細胞を72の間培養し、MTTアッセイによって細胞生存率を測定した。図16及び16Bのデータは、化合物ALB−188540(図16A)とALB−185643(図16B)がBxPC3細胞の生存率に関して、化合物ALB−185357と同様の効果を有していたことを示している。
様々な用量のALB−185357の存在下もしくは不存在下で細胞を72の間培養し、MTTアッセイによって(図17及び図18)、または細胞数を計測することによって(図19)、細胞生存率を測定した。MTTアッセイの結果は図17及び18に、細胞計数の結果は図19に示されている。このデータは、ALB−185357が様々ながん細胞種の生存を阻害することを示している。
様々な用量のALB−185357の存在下もしくは不存在下で細胞を72の間培養し、タンパク質レベルをウエスタンで測定した。データは、ALB−185357によって調節されると見込まれる経路が、実際に薬剤によって調節されることを示している。図21から分かるように、化合物ALB−185357は、MIA PaCa−2膵がん細胞株中で、予測されている標的のヒストンアセチル化とGSK−3βのリン酸化/阻害を、用量に依存して促進する。
様々な用量のALB−185357の存在下もしくは不存在下で細胞を72の間培養し、タンパク質レベルをウエスタンで測定(図22A)し、マトリゲル浸潤チャンバー中で細胞浸潤を測定した(図22B)。図22A中のデータは、ALB−185357が細胞の転移及び治療抵抗性を仲介するタンパク質をダウンレギュレーションすることを示している。図22B中のデータは、がん細胞の浸潤能力がダウンレギュレーションされることを示している。
Kras及びp53変異、並びに自然発症した膵臓腺がんを有するKPCマウスに、生後8週から死亡まで1週間に3回、5mg/KgのALB185357を腹腔内注射した。図23から分かるように、化合物ALB−185357は進行した膵がんを有する動物の生存率を向上させる。
Claims (107)
- 式(IV)の化合物:
式中、L1及びL2は、独立してリンカーであり;R1は、それぞれ任意選択的に置換されていてもよい、芳香族部位、アルキル、アシル、シクリル、またはヘテロシクリルであり;R2は、それぞれ任意選択的に置換されていてもよい、水素、低級アルキル、シクリル、ヘテロシクリル、アリール、またはヘテロアリールであり;R3は、存在しないか、または任意選択的に置換されていてもよい芳香族部位であり;pは、0、1、2、3、4、5、6、7、8、9、または10であり;−L1R1はチアジアゾリジン環の1つの窒素と結合しており、−(CH2)p−R3−L2−C(O)NHOR2はチアジアゾリジン環の他方の窒素と結合している。 - 粒子と結合している、請求項1〜13のいずれか1項に記載の化合物。
- 前記粒子が磁性粒子である、請求項14に記載の化合物。
- 開裂可能な連結基を含むリンカーを介して粒子と結合している、請求項14または請求項15に記載の化合物。
- 前記開裂可能な連結基が酵素によって切断される、請求項16に記載の化合物。
- 前記開裂可能な連結基が、がんまたは腫瘍中に多く存在する酵素によって切断される、請求項17に記載の化合物。
- 前記開裂可能な連結基が、がんまたは腫瘍中に多く存在するペプチダーゼによって切断される、請求項18に記載の化合物。
- 前記開裂可能な連結基が、カテプシンGの開裂可能な基質である、請求項19に記載の化合物。
- HDACとGSK3βの二重阻害剤を含有する組成物。
- 前記二重阻害剤が請求項1〜20のいずれか1項に記載の化合物である、請求項21に記載の組成物。
- 薬学的に許容可能な担体または賦形剤を更に含有する、請求項21に記載の組成物。
- 局所投与用に、脈管内投与用に、静脈内投与用に、動脈内投与用に、腫瘍内投与用に、筋肉内投与用に、皮下投与用に、腹腔内投与用に、鼻腔内投与用に、または経口投与用に製剤される、請求項21に記載の組成物。
- 抗がん治療剤を更に含有する、請求項21に記載の組成物。
- 前記抗がん治療剤が化学療法剤である、請求項25に記載の組成物。
- 以下の段階を含む、対象の症状の治療方法、対象の症状の予防方法、対象の発症の可能性の低減方法、対象の症状の重症度の低減方法、及び/または対象の症状の進行の鈍化方法:
HDACとGSK3βの二重阻害剤の治療有効量を対象に投与する段階であって、それによって対象の症状を治療する、対象の症状を予防する、対象の発症の可能性を低減させる、対象の症状の重症度を低減させる、及び/または対象の症状の進行を鈍化させる、段階。 - 前記症状が、がんまたは腫瘍である、請求項27に記載の方法。
- 前記症状が、膵がんである、請求項28に記載の方法。
- 前記対象がヒトである、請求項27に記載の方法。
- 前記二重阻害剤が請求項1〜請求項20のいずれか1項に記載の化合物である、請求項27に記載の方法。
- 前記二重阻害剤が局所的に、脈管内に、静脈内に、動脈内に、腫瘍内に、筋肉内に、皮下に、腹腔内に、鼻腔内に、または経口的に投与される、請求項27に記載の方法。
- 前記二重阻害剤が、約0.001〜0.01、0.01〜0.1、0.1〜0.5、0.5〜5、5〜10、10〜20、20〜50、50〜100、100〜200、200〜300、300〜400、400〜500、500〜600、600〜700、700〜800、800〜900、もしくは900〜1000mg/kg、またはこれらの組み合わせで投与される、請求項27に記載の方法。
- 前記二重阻害剤が、約0.001〜0.01、0.01〜0.1、0.1〜0.5、0.5〜5、5〜10、10〜20、20〜50、50〜100、100〜200、200〜300、300〜400、400〜500、500〜600、600〜700、700〜800、800〜900、もしくは900〜1000μg/kg、またはこれらの組み合わせで投与される、請求項27に記載の方法。
- 前記二重阻害剤が、およそ、1日に1〜3回、1週間に1〜7回、または1か月に1〜9回投与される、請求項27に記載の方法。
- 前記二重阻害剤が、約1〜10日間、10〜20日間、20〜30日間、30〜40日間、40〜50日間、50〜60日間、60〜70日間、70〜80日間、80〜90日間、90〜100日間、1〜6か月間、6〜12か月間、または1〜5年間投与される、請求項27に記載の方法。
- 追加的な抗がん療法を行う段階を更に含む、請求項2727に記載の方法。
- 前記二重阻害剤と前記追加的な抗がん療法が、同時にまたは逐次的に施される、請求項37に記載の方法。
- 前記追加的な抗がん療法が施される、施されている最中、または施された後に、前記二重阻害剤が投与される、請求項37に記載の方法。
- 前記追加的な抗がん療法が、外科手術、放射線療法(放射線治療)、生物学的療法、免疫療法、化学療法、及びこれらの任意の組み合わせからなる群から選択される、請求項37に記載の方法。
- 前記追加的な抗がん療法が、前記対象に抗がん治療剤を投与することを含む、請求項40に記載の方法。
- 前記二重阻害剤と前記抗がん治療剤が、1つの組成物中で提供される、請求項41に記載の方法。
- 前記二重阻害剤と前記抗がん治療剤が、別個の組成物中で提供される、請求項41に記載の方法。
- 前記抗がん治療剤が化学療法剤である、請求項41に記載の方法。
- 前記二重阻害剤が磁性粒子と結合しており、前記方法が、磁場を使用して二重阻害剤をがんまたは腫瘍へと導く段階を更に含む、請求項27に記載の方法。
- HDACとGSK3βの二重阻害剤;及び
対象の症状を治療するための、対象の症状を予防するための、対象の発症の可能性を低減させるための、対象の症状の重症度を低減するための、及び/または対象の症状の進行を鈍化させるための、前記二重阻害剤の使用のための指示書
を含む、対象の症状を治療するための、対象の症状を予防するための、対象の発症の可能性を低減させるための、対象の症状の重症度を低減するための、及び/または対象の症状の進行を鈍化させるための、キット。 - 前記HDACとGSK3βの二重阻害剤が、請求項1〜20のいずれか1項に記載の化合物である、請求項46項に記載のキット。
- 抗がん治療剤を更に含む、請求項46に記載のキット。
- 前記抗がん治療剤が化学療法剤である、請求項48に記載のキット。
- HDAC阻害剤とGSK3β阻害剤とを含有する組成物。
- 前記HDAC阻害剤が、SAHA、TSA、TPX、MS−275、バルプロ酸、もしくはCHAP31、またはこれらの機能的な等価体、類似体、誘導体もしくは塩、またはこれらの任意の組み合わせからなる群から選択される、請求項50に記載の組成物。
- 前記GSK3β阻害剤が、SB216763、TDZD−8、チデグルシブ(NP−12)、またはこれらの機能的な等価体、類似体、誘導体もしくは塩、またはこれらの任意の組み合わせからなる群から選択される、請求項50に記載の組成物。
- 前記HDAC阻害剤及び/または前記GSK3β阻害剤が、約0.001〜0.01、0.01〜0.1、0.1〜0.5、0.5〜5、5〜10、10〜20、20〜50、50〜100、100〜200、200〜300、300〜400、400〜500、500〜600、600〜700、700〜800、800〜900、もしくは900〜1000mg/kg、またはこれらの組み合わせである、請求項50に記載の組成物。
- 前記HDAC阻害剤及び/または前記GSK3β阻害剤が、約0.001〜0.01、0.01〜0.1、0.1〜0.5、0.5〜5、5〜10、10〜20、20〜50、50〜100、100〜200、200〜300、300〜400、400〜500、500〜600、600〜700、700〜800、800〜900、もしくは900〜1000μg/kg、またはこれらの組み合わせである、請求項50に記載の組成物。
- 薬学的に許容可能な賦形剤または担体を更に含有する、請求項50に記載の組成物。
- 局所投与用に、脈管内投与用に、静脈内投与用に、動脈内投与用に、腫瘍内投与用に、筋肉内投与用に、皮下投与用に、腹腔内投与用に、鼻腔内投与用に、または経口投与用に製剤される、請求項50に記載の組成物。
- 抗がん治療剤を更に含有する、請求項50に記載の組成物。
- 前記抗がん治療剤が化学療法剤である、請求項50に記載の組成物。
- 前記HDAC阻害剤と前記GSK3βのうちの少なくとも1つが粒子と結合している、請求項50に記載の組成物。
- 前記粒子が磁性粒子である、請求項59に記載の組成物。
- 前記HDAC阻害剤及び/または前記GSK3βが、開裂可能な連結基を含むリンカーを介して前記粒子と結合している、請求項59または請求項60に記載の組成物。
- 前記開裂可能な連結基が酵素によって切断される、請求項61に記載の組成物。
- 前記開裂可能な連結基が、がんまたは腫瘍中に多く存在する酵素によって切断される、請求項62に記載の組成物。
- 前記開裂可能な連結基が、がんまたは腫瘍中に多く存在するペプチダーゼによって切断される、請求項63に記載の組成物。
- 前記開裂可能な連結基が、カテプシンGの開裂可能な基質である、請求項64に記載の組成物。
- 以下の段階を含む、対象の症状の治療方法、対象の症状の予防方法、対象の発症の可能性の低減方法、対象の症状の重症度の低減方法、及び/または対象の症状の進行の鈍化方法:
HDAC阻害剤及びGSK3β阻害剤の治療有効量を対象に投与する段階であって、それによって対象の症状を治療する、対象の症状を予防する、対象の発症の可能性を低減させる、対象の症状の重症度を低減させる、及び/または対象の症状の進行を鈍化させる、段階。 - 前記症状が、がんまたは腫瘍である、請求項66に記載の方法。
- 前記症状が、膵がんである、請求項67に記載の方法。
- 前記対象がヒトである、請求項66に記載の方法。
- 前記HDAC阻害剤と前記GSK3β阻害剤が、1つの組成物中で提供される、請求項66に記載の方法。
- 前記HDAC阻害剤と前記GSK3β阻害剤が、別個の組成物中で提供される、請求項66に記載の方法。
- 前記HDAC阻害剤と前記GSK3β阻害剤が同時にまたは逐次的に投与される、請求項66に記載の方法。
- 前記GSK3β阻害剤の投与前、投与中、または投与後に、前記HDAC阻害剤が投与される、請求項66に記載の方法。
- 前記HDAC阻害剤が、SAHA、TSA、TPX、MS−275、バルプロ酸、もしくはCHAP31、またはこれらの機能的な等価体、類似体、誘導体もしくは塩、またはこれらの組み合わせである、請求項66に記載の方法。
- 前記GSK3β阻害剤が、SB216763、TDZD−8、もしくはチデグルシブ(NP−12)、またはこれらの機能的な等価体、類似体、誘導体もしくは塩、またはこれらの組み合わせである、請求項66に記載の方法。
- 前記HDAC阻害剤及び/または前記GSK3β阻害剤が、局所的に、脈管内に、静脈内に、動脈内に、腫瘍内に、筋肉内に、皮下に、腹腔内に、鼻腔内に、または経口的に投与される、請求項66に記載の方法。
- 前記HDAC阻害剤及び/または前記GSK3β阻害剤が、約0.001〜0.01、0.01〜0.1、0.1〜0.5、0.5〜5、5〜10、10〜20、20〜50、50〜100、100〜200、200〜300、300〜400、400〜500、500〜600、600〜700、700〜800、800〜900、もしくは900〜1000mg/kg、またはこれらの組み合わせで投与される、請求項66に記載の方法。
- 前記HDAC阻害剤及び/または前記GSK3β阻害剤が、約0.001〜0.01、0.01〜0.1、0.1〜0.5、0.5〜5、5〜10、10〜20、20〜50、50〜100、100〜200、200〜300、300〜400、400〜500、500〜600、600〜700、700〜800、800〜900、もしくは900〜1000μg/kg、またはこれらの組み合わせで投与される、請求項66に記載の方法。
- 前記HDAC阻害剤及び/または前記GSK3β阻害剤が、およそ、1日に1〜3回、1週間に1〜7回、または1か月に1〜9回投与される、請求項66に記載の方法。
- 前記HDAC阻害剤及び/または前記GSK3β阻害剤が、約1〜10日間、10〜20日間、20〜30日間、30〜40日間、40〜50日間、50〜60日間、60〜70日間、70〜80日間、80〜90日間、90〜100日間、1〜6か月間、6〜12か月間、または1〜5年間投与される、請求項66に記載の方法。
- 追加的な抗がん療法を行う段階を更に含む、請求項6627に記載の方法。
- 前記HDAC阻害剤、前記GSK3β阻害剤、及び前記追加的な抗がん療法が、同時にまたは逐次的に施される、請求項81に記載の方法。
- 前記追加的な抗がん療法が施される前、施されている最中、または施された後に、前記HDAC阻害剤及び/または前記GSK3β阻害剤が投与される、請求項81に記載の方法。
- 前記追加的な抗がん療法が、外科手術、放射線療法(放射線治療)、生物学的療法、免疫療法、化学療法、及びこれらの任意の組み合わせからなる群から選択される、請求項81に記載の方法。
- 前記追加的な抗がん療法が、前記対象に抗がん治療剤を投与することを含む、請求項84に記載の方法。
- 前記HDAC阻害剤、前記GSK3β阻害剤、及び前記化学療法剤が、別個の組成物中で提供される、請求項85に記載の方法。
- 前記HDAC阻害剤、前記GSK3β阻害剤、及び前記抗がん治療剤のうちの少なくとも2つが、1つの組成物中で提供される、請求項85に記載の方法。
- 前記HDAC阻害剤、前記GSK3β阻害剤、及び前記抗がん治療剤の3つ全てが1つの組成物中で提供される、請求項87に記載の方法。
- 前記抗がん治療剤が化学療法剤である、請求項85に記載の方法。
- 前記HDAC阻害剤と前記GSK3β阻害剤のうちの少なくとも1つが粒子と結合している、請求項66に記載の方法。
- 前記粒子が磁性粒子である、請求項90に記載の方法。
- 前記HDAC阻害剤及び/または前記GSK3βが、開裂可能な連結基を含むリンカーを介して前記粒子と結合している、請求項90または請求項91に記載の方法。
- 前記開裂可能な連結基が酵素によって切断される、請求項92に記載の方法。
- 前記開裂可能な連結基が、がんまたは腫瘍中に多く存在する酵素によって切断される、請求項93に記載の方法。
- 前記開裂可能な連結基が、がんまたは腫瘍中に多く存在するペプチダーゼによって切断される、請求項94に記載の方法。
- 前記開裂可能な連結基が、カテプシンGの開裂可能な基質である、請求項95に記載の方法。
- 前記HDAC阻害剤と前記GSK3βのうちの少なくとも1つが磁性粒子と結合しており、前記方法が、磁場を使用して前記HDAC阻害剤及び/または前記GSK3βをがんまたは腫瘍へと導く段階を更に含む、請求項68に記載の方法。
- HDAC阻害剤;
GSK3β阻害剤;及び
対象の症状を治療するための、対象の症状を予防するための、対象の発症の可能性を低減させるための、対象の症状の重症度を低減するための、及び/または対象の症状の進行を鈍化させるための、前記HDAC阻害剤及び前記GSK3β阻害剤の使用のための指示書
を含む、対象の症状を治療するための、対象の症状を予防するための、対象の発症の可能性を低減させるための、対象の症状の重症度を低減するための、及び/または対象の症状の進行を鈍化させるための、キット。 - 抗がん治療剤を更に含む、請求項98に記載のキット。
- 前記抗がん治療剤が化学療法剤である、請求項99に記載のキット。
- 前記HDAC阻害剤と前記GSK3βのうちの少なくとも1つが粒子と結合している、請求項98に記載のキット。
- 前記粒子が磁性粒子である、請求項101に記載のキット。
- 前記HDAC阻害剤及び/または前記GSK3βが、開裂可能な連結基を含むリンカーを介して前記粒子と結合している、請求項101に記載のキット。
- 前記開裂可能な連結基が酵素によって切断される、請求項102に記載のキット。
- 前記開裂可能な連結基が、がんまたは腫瘍中に多く存在する酵素によって切断される、請求項103に記載のキット。
- 前記開裂可能な連結基が、がんまたは腫瘍中に多く存在するペプチダーゼによって切断される、請求項104に記載のキット。
- 前記開裂可能な連結基が、カテプシンGの開裂可能な基質である、請求項106に記載のキット。
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ES2960601T3 (es) | 2024-03-05 |
JP7015856B2 (ja) | 2022-02-03 |
KR20170015507A (ko) | 2017-02-08 |
AU2021201667B2 (en) | 2022-11-17 |
JP6663863B2 (ja) | 2020-03-13 |
CA2950774C (en) | 2023-03-21 |
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AU2023200895A1 (en) | 2023-03-16 |
US10836735B2 (en) | 2020-11-17 |
US20180297965A1 (en) | 2018-10-18 |
CN106794175B (zh) | 2020-06-09 |
US20170121297A1 (en) | 2017-05-04 |
AU2021201667A1 (en) | 2021-04-08 |
AU2015274334A1 (en) | 2016-12-15 |
US20210276964A1 (en) | 2021-09-09 |
US20190194152A1 (en) | 2019-06-27 |
EP3154544A1 (en) | 2017-04-19 |
CN106794175A (zh) | 2017-05-31 |
US10029997B2 (en) | 2018-07-24 |
AU2015274334B2 (en) | 2020-12-17 |
KR102567244B1 (ko) | 2023-08-16 |
EP4306173A3 (en) | 2024-04-10 |
MX2016016507A (es) | 2017-04-27 |
JP2020090537A (ja) | 2020-06-11 |
US10266505B2 (en) | 2019-04-23 |
CA2950774A1 (en) | 2015-12-17 |
EP3154544A4 (en) | 2017-12-20 |
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