JP6264685B2 - マルチキナーゼ阻害剤、抗癌剤、抗転移剤、薬剤耐性抑制剤、疼痛抑制剤及び止痒薬 - Google Patents
マルチキナーゼ阻害剤、抗癌剤、抗転移剤、薬剤耐性抑制剤、疼痛抑制剤及び止痒薬 Download PDFInfo
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Trk Aは、乳癌の増殖と転移の促進に関与していることが報告されている(非特許文献8)。現在、Trk Aに対する分子標的治療薬の開発が進められているが、医薬品として承認されたものはない。本発明では、TrkAを発現する癌の増殖を抑制する治療薬(抗癌剤)として有用なTrk A阻害剤を提供することを目的とする。
Li T., Zhang H., Identification and comparative determination of rhodionin in traditional tibetan medicinal plants of fourteen Rhodiola species by high-performance liquid chromatography-photodiode array detection and electrospray ionization-mass spectrometry, Chem Pharm Bull, 56, 807-814, 2008. Struijs K., et al., The flavonoid herbacetin diglucoside as a constituent of the lignin macromolecule from flaxseed hulls, Phytochemistry, 68, 1227-1235, 2007. Mounnissamy V.M., et al., Antibacterial activity of gossypetin isolated from hibiscus sabdariffa, The Antiseptic, 99, 81-82, 2002. Qiu, S.-X., et al., Isolation and characterization of flaxseed (Linum sitatissimum) constituents, Pharmaceutical Biology, 37, 1-7, 1999. Jeong H.J., et al., Neuraminidase inhibitory activities of flavonols isolated from Rhodiola rosea roots and their in vitro anti-influenza viral activities, Bioorganic & Medicinal Chemistry, 17, 6816-6823, 2009. Gedara S.R., et al., New erythroxane-type diterpenoids from Fagoniaboveana (Hadidi) Hadidi& Graf,Zeitschrift fur Naturforschung C Journal of Biosciences, 58, 23-32, 2003. Choe K.I., et al., The antioxidant and anti-inflammatory effects of phenolic compounds isolated from the root of Rhodiola sachalinensis A. BOR, Molecules, 17, 11484-11494, 2012. Rankin S.M., et al., The modification of low density lipoprotein by the flavonoids myricetin and Gossypetin, Biochem Pharmacol, 45, 67-75, 1993. Paoletta S., et al., Screening of herbal constituents for aromatase inhibitory activity, Bioorg Med Chem, 16, 8466-8470, 2008.
癌細胞の運動能と転移能は高い相関関係があり、癌細胞の運動能を抑制することによって転移を抑制することができる。
実施例2 HGF-METシグナルに対するヘルバセチンの効果
HGFにより誘導されるMETのチロシンリン酸化に対するヘルバセチンの効果をMDA-MB-231細胞を用いて解析した。また、比較対照として、ヘルバセチンの構造に類似したフラボノイドである、ケンフェロール、アピゲニン、及びイソスクテラレインを用いた。
実施例3 ヘルバセチンと各種フラボノイドのMETチロシンキナーゼ活性阻害効果の解析
1)METキナーゼドメインの組換えタンパク質と合成基質ペプチドを用いたキナーゼ阻害アッセイを行った。20 mM HEPES,0.01% Triton X-100,2 mM DTT,25 μM ATP,5 mM MgCl2,pH7.5に0.94 nM 組換えMETキナーゼドメイン,1 μM Srctide及び0.001〜30 μM ヘルバセチンを添加し、室温で1時間反応させた。基質ペプチドと生成したリン酸化ペプチド量をLab Chip 3000(Caliper Lifesciences)を用いて測定した。統計解析ソフトウエア(GraphPad Prism 5)を用いてヘルバセチンの添加濃度に対するリン酸化ペプチドの生成阻害率のプロットに対する4パラメーターロジスティック曲線の近似式を求め、そのパラメーターよりIC50値を算出した。その結果、ヘルバセチンは,濃度依存的にMETのチロシンキナーゼ活性を阻害することが明らかとなり、そのIC50値は、1.284 μMであった(図5)。
実施例4 ヘルバセチンの網羅的キナーゼ阻害活性の解析
ヘルバセチンのキナーゼ阻害活性の特異性を解明するために、受容体型チロシンキナーゼと細胞周期に関連したキナーゼ等、50種のキナーゼについて網羅的な解析を行った。
実施例5 ヒト急性骨髄性白血病細胞由来MV4-11細胞の増殖に対するヘルバセチンの効果
FLT3が恒常的に活性化しているヒト急性骨髄性白血病細胞由来MV4-11細胞を10%血清添加培地で懸濁し、48ウェルプレートに播種し、ヘルバセチンを最終濃度0-40 μg/mLとなるように添加し、3日間培養した後、WSTアッセイで生細胞数を定量した。その結果、MV4-11細胞の細胞数は、ヘルバセチンの添加濃度に依存して減少しており、そのIC50値は17.7 μMであった(図6)。
実施例6 ヒト肝癌由来HuH-7細胞のAurora kinase B及び細胞周期に対するヘルバセチンの効果
1)Aurora kinase B陽性であるヒト肝癌由来HuH-7細胞を用いて、ヘルバセチンのAurora kinase Bに対する効果として、Aurora kinase Bの発現量とAurora kinase Bの基質であるHistone-H3のリン酸化について解析した。10%血清添加培地に懸濁したHuH-7細胞をディッシュに播種し、24時間培養した。0-20 μg/mLヘルバセチン及び10%血清添加培地で6時間培養し、PBSで洗浄した後、タンパク質抽出用細胞溶解液で細胞を溶解した。細胞の溶解液についてSDS-PAGEを行い、抗リン酸化Histone-H3抗体、抗Aurora kinase B抗体を用いたウエスタンブロッティングで検出した。その結果、ヘルバセチンの添加濃度依存的にHistone-H3のリン酸化は抑制されたが、Aurora kinase Bの発現量は変化しなかった(図7(a)、図7(b))。
実施例7 ヒト肝癌由来HuH-7細胞株の増殖に対するヘルバセチンの効果
HuH-7細胞の増殖に対するヘルバセチンの効果を解析するため、10%血清添加培地に懸濁したHuH-7細胞を48ウェルプレートに播種し、24時間培養した。0〜40 μg/mLヘルバセチン添加培地で3日間培養した後、WSTアッセイで生細胞数を定量した。その結果、HuH-7細胞の増殖は、ヘルバセチンの添加濃度依存的に抑制された(図9)。
実施例8 ヒト肝癌由来HuH-7細胞移植ヌードマウスの腫瘍増殖に対するヘルバセチンの効果
腫瘍増殖に対するヘルバセチンの効果を解析した。Balb/cヌードマウス(チャールス・リバー)にHuH-7細胞を皮下移植し、1週間後、腫瘍形成を確認し、コントロール群とヘルバセチン投与群、各6匹ずつに分けた。1日1回、コントロール群は滅菌水を経口投与し、ヘルバセチン投与群は、35 mg/kgのヘルバセチンを経口投与した。経時的に腫瘍サイズとマウスの体重を測定し、20日目にマウスを過麻酔下に屠殺して、腫瘍を回収した。腫瘍重量は、ヘルバセチン投与群はコントロール群と比較して有意に低下していた(図10(a)、図11(a))が、マウスの体重は実験期間を通して、コントロール群及びヘルバセチン投与群で有意差はなかった(図10(b)、図11(b))。
実施例9 ラット副腎髄質クロム親和性細胞腫PC12細胞のNGFによって誘導されるTrkAリン酸化及び神経突起伸長に対するヘルバセチンの抑制効果
NGFにより誘導されるTrkAのチロシンリン酸化及び神経突起伸長に対するヘルバセチンの効果についてPC12細胞を用いて解析した。
実施例10 マウスのホルマリン誘発性疼痛に対するヘルバセチンの疼痛抑制効果
ヘルバセチンがin vivoで疼痛抑制効果を有するのかどうかを明らかにするために、ホルマリン試験を行った。ヘルバセチン(50, 100, 150 mg/kg)をマウス(n=8)の腹腔内に投与し90分後に、2.5%ホルマリン溶液20 μLを左後肢足裏皮下に投与した。足を舐める、噛むなどの疼痛関連行動を経時的に測定した。ホルマリン試験は2相性の反応を示す。第1相目(0-5 分間)の反応は、ホルマリンよる知覚神経主末へ直接刺激による痛みを反映し、第2相目(15-45 分間)の反応は、ホルマリン組織侵害で生じた炎症による痛みを反映する。モルヒネのような中枢性鎮痛薬は、第1相目及び第2相の両方を抑制し、非ステロイド性抗炎症薬(NSAIDs)は、第2相のみを抑制する。ヘルバセチンは、第1相目の反応については抑制傾向を示したが有意差はなかった。一方、第2相目の反応については濃度依存的に抑制し、100〜150 mg/kgでは、有意に疼痛行動を抑制した(図15)。
実施例11 ヘルバセチンと類似構造を有するゴシペチンのキナーゼ阻害特性の解析
式7に示されるゴシペチンは、ヘルバセチンと極めて構造が類似しているフラボノールである。ヘルバセチンで見出されたマルチキナーゼ阻害作用をゴシペチンも有しているのかを解析した。
Claims (18)
- 式1を備えるフラボノールを有効成分として含有するマルチキナーゼ阻害剤。
- 前記フラボノールの配糖体を有効成分として含有する請求項1に記載のマルチキナーゼ阻害剤。
- METを発現する胃癌、食道癌、大腸癌、肺癌、乳癌、肝癌、腎癌、膵臓癌、及び卵巣癌の増殖及び再発転移抑制のための治療、MET発現が原因の耐性非小細胞肺癌の治療、Aurora kinaseを発現する癌の増殖抑制のための治療、FLT3活性化急性骨髄性白血病の治療、並びに、TrkAを発現する癌の治療、TrkAが仲介する疼痛及び掻痒の治療のために用いられる請求項1又は2に記載のマルチキナーゼ阻害剤。
- 前記フラボノールがMETを阻害する請求項1乃至3の何れか1項に記載のマルチキナーゼ阻害剤。
- 前記フラボノールがAurora kinaseを阻害する請求項1乃至3の何れか1項に記載のマルチキナーゼ阻害剤。
- 前記フラボノールがFLT3を阻害する請求項1乃至3の何れか1項に記載のマルチキナーゼ阻害剤。
- 前記フラボノールがTrk Aを阻害する請求項1乃至3の何れか1項に記載のマルチキナーゼ阻害剤。
- 式1を備えるフラボノールを有効成分として含有するMETを発現する癌の抗癌剤、抗転移剤及び薬剤耐性抑制剤。
- 前記フラボノールの配糖体を有効成分として含有する請求項8に記載のMETを発現する癌の抗癌剤、抗転移剤及び薬剤耐性抑制剤。
- 前記フラボノールがMETのチロシンリン酸化を阻害することによりMET発現癌の治療に用いられる請求項8又は9に記載のMET発現癌の抗癌剤、抗転移剤及び薬剤耐性抑制剤。
- 式1を備えるフラボノールを有効成分として含有する、Aurora kinaseを発現する癌の増殖を抑制する抗癌剤。
- 前記フラボノールの配糖体を有効成分として含有する請求項11に記載の抗癌剤。
- 式1を備えるフラボノールを有効成分として含有する、FLT3活性化急性骨髄性白血病の治療のために用いられる抗癌剤。
- 前記フラボノールの配糖体を有効成分として含有する請求項13に記載の抗癌剤。
- 式1を備えるフラボノールを有効成分として含有する、TrkAを発現する癌の抗癌剤、抗転移剤。
- 前記フラボノールの配糖体を有効成分として含有する請求項15に記載の抗癌剤、抗転移剤。
- 式1を備えるフラボノールを有効成分として含有する、TrkAが仲介する疼痛及び掻痒の治療のために用いられる疼痛抑制剤及び止痒薬。
- 前記フラボノールの配糖体を有効成分として含有する請求項17に記載の疼痛抑制剤及び止痒薬。
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