JP2022117995A - プロテアソーム阻害剤 - Google Patents
プロテアソーム阻害剤 Download PDFInfo
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- JP2022117995A JP2022117995A JP2022084418A JP2022084418A JP2022117995A JP 2022117995 A JP2022117995 A JP 2022117995A JP 2022084418 A JP2022084418 A JP 2022084418A JP 2022084418 A JP2022084418 A JP 2022084418A JP 2022117995 A JP2022117995 A JP 2022117995A
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- Prior art keywords
- amino
- boronic acid
- compound
- acetyl
- methylbutyl
- Prior art date
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
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- 238000001228 spectrum Methods 0.000 description 1
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- 238000010561 standard procedure Methods 0.000 description 1
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- UVFAEQZFLBGVRM-MSMWPWNWSA-N succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CCC(O)=O)CC(C)C)C(=O)NC=1C=C2OC(=O)C=C(C)C2=CC=1)C1=CC=C(O)C=C1 UVFAEQZFLBGVRM-MSMWPWNWSA-N 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- 230000009466 transformation Effects 0.000 description 1
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Abstract
Description
またはその薬学的に許容される塩もしくはボロン酸無水物であり、式中、Z1およびZ2は、それぞれ独立してヒドロキシ、アルコキシ、アリールオキシ、もしくはアラルコキシであるか、またはZ1およびZ2は共に、ボロン酸錯化剤に由来する部分を形成し、
環Aは、
例えば、本願発明は以下の項目を提供する。
(項目1)
式(I)の化合物:
またはその薬学的に許容される塩もしくはボロン酸無水物であって、
式中、Z1およびZ2は、それぞれ独立してヒドロキシ、アルコキシ、アリールオキシ、もしくはアラルコキシであるか、またはZ1およびZ2は共に、ボロン酸錯化剤に由来する部分を形成し、
環Aは、
から成る群より選択される、
化合物。
(項目2)
[(1R)-1-({[(2,3-ジフルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(5-クロロ-2-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(3,5-ジフルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2,5-ジフルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2-ブロモベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-(([(2-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2-クロロ-5-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(4-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(3,4-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(3-クロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2,5-ジクロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(3,4-ジクロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(3-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2-クロロ-4-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-(([(2,3-ジクロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2-クロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2,4-ジフルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(4-クロロ-2-フルオロベンゾイル)アミノ]アセチル)アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(4-クロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2,4-ジクロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、および
[(1R)-1-({[(3,5-ジクロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、またはその薬学的に許容される塩もしくはボロン酸無水物、から成る群より選択される、項目1に記載の化合物。
(項目3)
[(1R)-1-({[(2,3-ジフルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(5-クロロ-2-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(3,5-ジフルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2,5-ジフルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2-ブロモベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2-クロロ-5-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(4-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(3,4-ジフルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(3-クロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2,5-ジクロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(3,4-ジクロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(3-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-l-({[(2-クロロ-4-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2,3-ジクロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(2-クロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-l-({[(2,4-ジフルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(4-クロロ-2-フルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-({[(4-クロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
[(1R)-1-(|[(2,4-ジクロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、および
[(1R)-1-({[(3,5-ジクロロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸、
から成る群より選択されるボロン酸化合物のマンニトールエステルである、項目1に記載の化合物。
(項目4)
項目1に記載の化合物と薬学的に許容される担体とを含む、医薬組成物。
(項目5)
癌を治療するための方法であって、項目3に記載の医薬組成物を、かかる治療を必要とする患者に投与する工程を含む、方法。
J. Am. Chem. Soc. 80:3611(1958)は、オリゴマーアリールボロン酸を報告している。
式(1)および(2)において、変数nは、0~約10、好ましくは0、1、2、3、または4の整数である。いくつかの実施形態では、ボロン酸無水物化合物は、式(2)の環状三量体(「ボロキシン」)を含み、式中、nは1である。変数Wは、式(3)を有する。
式(I)の化合物は、当業者に既知の方法によって調製することができる。例えば、Adams et. alの米国特許第5,780,454号、Pickersgill et al.の国際特許公開第 2005/097809号を参照されたい。例示的な合成経路は、以下のスキーム1に記載されている。
化合物iとN-保護グリシン(ii)とのカップリング、およびそれに続くN末端脱保護は、化合物iiiをもたらす。好適な保護基(PG)の例としては、例えば、ホルミル、アセチル(Ac)、スクシニル(Suc)、およびメトキシスクシニル等のアシル保護基、ならびにtert-ブトキシカルボニル(Boc)、ベンジルオキシカルボニル(Cbz)、およびフルオレニルメトキシカルボニル(Fmoc)等のウレタン保護基が挙げられるがこれに限定されない。ペプチドカップリング反応は、化合物iiの例えば、O-(N-ヒドロキシこはく酸イミド)エステル等のカルボン酸部分の活性化エステルへの前変換、それに続く化合物iでの処理によって行うことができる。代替的に、活性化エステルは、カルボン酸をペプチドカップリング試薬と接触させることによって、原位置で生成することができる。好適なペプチドカップリング試薬の例としては、例えば、ジシクロヘキシルカルボジイミド(DCC)またはl-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド(EDC)等のカルボジイミド試薬、例えば、ベンゾトリアゾール-l-イルオキシトリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスファート(BOP)等のホスホニウム試薬、および例えば、O-(lH-ベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウムテトラフルオロボラート(TBTU)等のウロニウム試薬が挙げられるがこれに限定されない。
代替的に、カップリング反応の順序は、スキーム2に示されるように逆であってもよい。したがって、O-保護グリシン(vi)を最初に置換安息香酸(ArCO2H)とカップリングし、その後エステル加水分解して、化合物viiを形成するさ。次いで、スキーム1に関して上に記載されるように、化合物iとのカップリングおよびボロン酸脱保護を行って、化合物vを得る。
本発明は、プロテアソームの強力な阻害剤である化合物を提供する。該化合物は、プロテアソームによるペプチド加水分解またはタンパク質分解を阻害するそれらの能力に関して、生体外または生体内で分析され得る。
分析LC-MS法
以下の勾配を使用して、Symmetry C18-3.5μm-4.6×50mmカラムでスペクトルを実行した。
溶媒A:2%イソプロピルアルコール、98%水、10mMのNH4OAc
溶媒B:75%アセトニトリル、25%メタノール、10mMのNH4OAc。
工程1:メチル[(2,3-ジフルオロベンゾイル)アミノ]アセテート
テトラヒドロフラン(5mL)中の2,3-ジフルオロ安息香酸(0.190g、1.2ミリモル)の溶液に、グリシンメチルエステル塩酸塩(0.150g、1.2ミリモル)、HOBt(0.162g、1.2ミリモル)、DIEA(0.209mL、1.2ミリモル)、およびEDCI(0.252g、1.3ミリモル)を添加した。反応混合物を一晩撹拌した。反応混合物を重炭酸ナトリウムの飽和溶液で反応停止し、生成物をDCM中に分離した。有機層を分離し、溶媒を除去することによって、メチル[(2,3-ジフルオロベンゾイル)アミノ]アセテートを得、それを精製することなく次の工程に使用した。
メタノール(7mL)中のメチル[(2,3-ジフルオロベンゾイル)アミノ]アセテート(0.250g、1.1ミリモル)の溶液に、水酸化リチウム(0.053g、2.2ミリモル)および水(3mL)を添加した。反応混合物を一晩撹拌した。混合物を水(20mL)で希釈し、1N HCl(5mL)で酸性化した。生成物をDCM/メタノール(4:1)中に分離した。有機層を硫酸ナトリウムで乾燥させ、溶媒を除去し、[(2,3-ジフルオロベンゾイル)アミノ]酢酸を得、それを精製することなく次の工程に使用した。
ジメチルホルムアミド(10mL)中の[(2,3-ジフルオロベンゾイル)アミノ]酢酸(0.205g、0.95ミリモル)の溶液に、TBTU(0.337g、1.0ミリモル)、およびそのトリフルオロアセタート塩としての(1R)-3-メチル-1-[(3aS,4S,6S,7aR)-3a,5,5-トリメチルヘキサヒドロ-4,6-メタノ-1,3,2-ベンゾジオキサボロール-2-イル]ブタン-1-アミン(0.362g、0.95ミリモル)を添加した。混合物を0℃まで冷却し、DIEA(0.498mL、2.9ミリモル)を滴下添加した。反応混合物を室温まで温め、一晩撹拌した。水(100mL)で反応を停止し、生成物をDCM中に分離した。有機層を硫酸ナトリウムで乾燥させ、溶媒を除去し、2,3-ジフルオロ-N-[2-({(1R)-3-メチル-1-[(3aR,4R,6R,7aS)-3a,5,5-トリメチルヘキサヒドロ-4,6-メタノ-1,3,2-ベンゾジオキサボロール-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミドを得た。
メタノール/1N HCl(1:1)(1.5mL)中の2,3-ジフルオロ-N-[2-({(1R)-3-メチル-1-[(3aR,4R,6R,7aS)-3a,5,5-トリメチルヘキサヒドロ-4,6-メタノ-1,3,2-ベンゾジオキサボロール-2-イル]ブチル}アミノ)2-オキソエチル]ベンズアミド(0.536g、1.2ミリモル)の溶液に、ヘプタノール(1mL)およびイソブチルボロネート(0.207g、2.0ミリモル)を添加した。反応混合物を一晩撹拌した。ヘプタノール層を分離し、メタノール/HCl層を濃縮した。粗生成物を逆相HPLCによって精製し、[(1R)-1-({[(2,3-ジフルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸を得た。
t-ブチルアルコール(2mL)および水(5mL)中の[(1R)-1-({[(2,3-ジフルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸(0.085g、0.26ミリモル)の溶液に、D-マンニトール(0.943g、5.2ミリモル)を添加した。溶液を温め、全てが溶解するまで撹拌した。次いで、溶液を冷凍し、溶媒を凍結乾燥によって除去し、[(1R)-1-({[(2,3-ジフルオロベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸.20D-マンニトール(I-1)(0.98g、97%)を得た。
工程1:tert-ブチル[2-({(1R)-3-メチル-1-[(3aS,4S,6S,7aR)-3a,5,5-トリメチルヘキサヒドロ-4,6-メタノ-1,3,2-ベンゾジオキサボロール-2-イル]ブチル}アミノ)-2-オキソエチル]カルバメート
トリフルオロアセタート塩としての(1R)-3-メチル-1-[(3aS,4S,6S,7aR)-3a,5,5-トリメチルヘキサヒドロ-4,6-メタノ-1,3,2-ベンゾジオキサボロール-2-イル]ブタン-1-アミン(4.9g、10.8ミリモル)の混合物に、N-・-(tert-ブトキシカルボニル)グリシン(1.98g、11.3ミリモル)を添加し、DCM(100mL)中のTBTU(3.81g、11.9ミリモル)に、DCM(25mL)中のDIEA(5.64mL、32.4ミリモル)の溶液を15分にわたって滴下添加した。反応混合物を一晩撹拌し、濃縮した。粗生成物をカラムクロマトグラフィによって精製し、tert-ブチル[2-({(1R)-3-メチル-1-[(3aS,4S,6S,7aR)-3a,5,5-トリメチルヘキサヒドロ-4,6-メタノ-1,3,2-ベンゾジオキサボロール-2-イル]ブチル}アミノ)-2-オキソエチル]カルバメート(2.5g、55%)を得た。
DCM(15mL)中のtert-ブチル[2-({(1R)-3-メチル-1-[(3aS,4S,6S,7aR)-3a,5,5-トリメチルヘキサヒドロ-4,6-メタノ-1,3,2-ベンゾジオキサボロール-2-イル]ブチル}アミノ)-2-オキソエチル]カルバメート(2.5g、5.9ミリモル)の溶液に、ジオキサン(5.9mL)中の4M HClを添加した。反応混合物を2時間撹拌し、濃縮し、2-アミノ-N-{(1R)-3-メチル-1-[(3aS,4S,6S,7aR)-3a,5,5-トリメチルヘキサヒドロ-4,6-メタノ-1,3,2-ベンゾジオキサボロール-2-イル]ブチル}アセトアミドを得、それを精製することなく次の工程に使用した。
DCM(2.25mL)中の2-ブロモ安息香酸(0.124g、0.62ミリモル)の溶液に、EDCI(0.119g、0.62ミリモル)、HOBt(0.084g、0.62ミリモル)、N-メチルモルホリン(0.185mL、1.68ミリモル)、および2-アミノ-N-{(1R)-3-メチル-1-[(3aS,4S,6S,7aR)-3a,5,5-トリメチルヘキサヒドロ-4,6-メタノ-1,3,2-ベンゾジオキサボロール-2-イル]ブチル}アセトアミド(0.2g、0.56ミリモル)を添加した。反応混合物を2時間撹拌し、濃縮した。残渣を水で希釈し、EtOAcで抽出した。有機溶液を混合し、塩水で洗浄し、MgSO4で乾燥させ、濾過し、濃縮した。粗生成物をカラムクロマトグラフィによって精製し、2-ブロモ-N-[2-({(1R)-3-メチル-1-[(3aS,4S,6S,7aR)-3a,5,5-トリメチルヘキサヒドロ-4,6-メタノ-1,3,2-ベンゾジオキサボロール-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミド(0.22g、78%)を得た。
メタノール/ヘキサン(1:1)(2.2mL)中の2-ブロモ-N-[2-({(1R)-3-メチル-1-[(3aS,4S,6S,7aR)-3a,5,5-トリメチルヘキサヒドロ-4,6-メタノ-1,3,2-ベンゾジオキサボロール-2-イル]ブチル}アミノ)-2-オキソエチル]ベンズアミド(0.220g、0.44ミリモル)の溶液に、(1mL、1.0ミリモル)およびイソブチルボロネート(0.078g、0.76ミリモル)を添加した。反応混合物を一晩撹拌した。反応混合物を濃縮し、逆相HPLCによって精製し、[(1R)-1-({[(2-ブロモベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸(0.119g、73%)を得た。
tert-ブチルアルコール(9mL)および水(15mL)中の[(1R)-1-({[(2-ブロモベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸(0.103g、0.28ミリモル)の溶液に、D-マンニトール(1.01g、5.5ミリモル)を添加した。溶液を温め、全てが溶解するまで撹拌した。次いで、溶液を冷凍し、溶媒を凍結乾燥によって除去し、[(1R)-1-({[(2-ブロモベンゾイル)アミノ]アセチル}アミノ)-3-メチルブチル]ボロン酸.20D-マンニトール(I-5)(0.92g、84%)を得た。
実施例2:20Sプロテアソームアッセイ
384ウェルの黒色マイクロタイタープレート中のDMSOに溶解した1μLの試験化合物に、ヒトPA28活性剤(Boston Biochem、最終12nM)とAc-WLA-AMC(β5選択的基質)(最終15μM)を含有する37℃で25μLのアッセイ緩衝剤、続いてヒト20Sプロテアソーム(Boston Biochem、最終0.25nM)を含有する37℃で25μLのアッセイ緩衝剤を添加した。アッセイ緩衝剤は、20mMのHEPES、0.5mMのEDTA、および0.01%のBSA、pH7.4から成る。続いて、反応物をBMG Galaxyプレートリーダ(37℃、励起380nm、放出460nm、ゲイン20)にかけた。0%阻害(DMSO)および100%阻害(10μMのボルテゾミブ)の対照と比較して、阻害の割合を計算した。
10%ウシ胎仔血清(Invitrogen)が添加された100μLの適切な細胞培養基(HCT-116用のMcCoy’s 5A、Invitrogen)中のHCT-116(1000)または他の腫瘍細胞を96ウェルの細胞培養プレートのウェルで播種し、プレートを37℃で96時間インキュベートする。MTTまたはWST試薬(10μL、Roche)を各ウェルに添加し、製造者によって説明されるように37℃で4時間インキュベートする。MTTに対して、製造者の使用説明書(Roche)に従って、代謝染料を一晩可溶化する。分光光度計(Molecular Devices)を使用して、MTTに対して595nm(主)および690nm(標準)で、およびWSTに対して450nmで、各ウェルの光学濃度を読み取る。MTTに対して、標準光学濃度値を主波長の値から引く。100%に設定されたDMSO対照からの値を使用して、阻害の割合を計算する。
1mLの26 3/8ゲージ針(Becton Dickinson Ref#309625)を使用して、雌CD-1ヌードマウス(5~8週齢、Charles River)の右背部側腹部にある皮下空間に、100μLのRPMI-1640培地(Sigma-Aldrich)中の解離直後のHCT-116(2-5×106)または他の腫瘍細胞を無菌注射する。代替的に、いくつかの異種移植片モデルは、腫瘍断片の連続継代を必要とする。これらの場合、麻酔(3-5%イソフロラン/酸素混合物)をかけたC.B-17/SCIDマウス(5~8週齢、Charles River)の右背部側腹部に、13ゲージトロカール(Popper&Sons 7927)を介して、腫瘍組織の小断片(約1mm3)を皮下移植する。接種の7日後から、バーニアカリパスを使用して週に2回、腫瘍を測定する。標準手順を使用して、腫瘍体積を計算する(0.5×(長さ×幅2))。腫瘍が、約200mm3の体積に達すると、マウスを治療群に無作為に割り付け、薬剤治療を受け始める。薬物動態/薬力学および最大耐量研究から得られた以前の結果に基づいて、各実験に対する投薬およびスケジュールを決定する。対照群は、いかなる薬剤も含まないビヒクルを受ける。典型的には、種々の用量およびスケジュールで、静脈内(27ゲージ針)、経口(20ゲージ給餌針)、または皮下(27ゲージ針)経路を介して、試験化合物(100~200μL)を投与する。腫瘍の大きさおよび体重を週に2回測定し、対照腫瘍が、約2000mm3に達した時に、研究を終了する。
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