JP2016537400A - 幹細胞調節ii - Google Patents
幹細胞調節ii Download PDFInfo
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- JP2016537400A JP2016537400A JP2016543268A JP2016543268A JP2016537400A JP 2016537400 A JP2016537400 A JP 2016537400A JP 2016543268 A JP2016543268 A JP 2016543268A JP 2016543268 A JP2016543268 A JP 2016543268A JP 2016537400 A JP2016537400 A JP 2016537400A
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Abstract
Description
本発明は、一般には、がん幹細胞を調節する組成物および方法に関する。より具体的には、本発明は、がん幹細胞を含むPKC−θ過剰発現細胞の増殖を阻害するための、化学療法薬または放射線照射のがん細胞に対する生物学的作用を強化するための、転移性がんを含むがんを治療するための、および/またはがんの再発を防止するための、タンパク質キナーゼC−θ阻害剤の使用に関する。
特記されない限り、本明細書に使用される技術的および科学的用語はすべて、本発明の属する分野の当業者によって一般に理解されるのと同じ意義を有する。本発明を実施または試験するのに、本明細書に記載の方法および材料と同様のまたは均等な方法および材料を用いることもできるが、好ましい方法および材料が記載されている。本発明の目的を達成するのに、次の用語を以下に定義する。
本発明は、乳がんがCSCに富んでおり、PKC−θがそれらのCSCにて、ならびにCSC以外の腫瘍細胞で過剰発現されるという決定にいくらか基づくものである。これらの知見に基づき、本発明者らは、乳がん、乳房CSCおよびCSC以外の乳房腫瘍細胞をPKC−θ阻害剤で処理し、該阻害剤が乳房CSCおよびCSC以外の腫瘍細胞の形成、増殖または維持を特異的に阻害し、乳房CSCのEMTを阻害し、および/または乳房CSCでのMETを刺激/誘発することを見出した。理論または操作モードで拘束するものではないが、PKC−θがそのシグナル化のレベルおよび乳房CSCを機能付けする後成的役割の両方で重要であり、この酵素の過剰発現が乳房CSCおよびCSC以外の腫瘍細胞の産生および維持だけでなく、一般にCSCおよびCSC以外の腫瘍細胞の産生を刺激することが提案されている。
PKC−θ阻害剤は、PKC−θの蓄積、機能または安定性を減らすか;PKC−θ遺伝子の発現を減少させる、いずれの活性剤も包含し、そのような阻害剤は、限定されるものではなく、小分子および巨大分子、例えば核酸、ペプチド、ポリペプチド、ペプチド模倣体、炭水化物、多糖類、リポ多糖類、脂質または他の有機(含炭素)または無機分子を包含する。
(1)例えば、ジンバンク受入番号(GenBank Accession Nos.)XM 005252496、XM 005252497、XM 005252498、およびXM 005252499で示されるヒトPKC−θヌクレオチド配列、(2)(1)において言及されるいずれか一つの配列と少なくとも70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99%の配列同一性を共有するヌクレオチド配列;(3)少なくとも低、中または高ストリンジェンシー条件下で、(1)において言及される配列とハイブリッド形成するヌクレオチド配列;(4)以下のアミノ酸配列:例えば、ジンペプト受入番号(GenPept Accession Nos.)XP 005252553、XP 005252554、XP 005252555およびXP 005252556で示されるヒトPKC−θアミノ酸配列のいずれか一つをコードするヌクレオチド配列;(5)(4)において言及されるいずれか一つの配列と少なくとも70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99%の配列類似性を共有するアミノ酸配列をコードするヌクレオチド配列;および(6)(4)において言及されるいずれか一つの配列と少なくとも70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99%の配列同一性を共有するアミノ酸配列をコードするヌクレオチド配列のいずれか一つに相当する核酸配列が挙げられる。
が挙げられる。
で示される化合物を包含し、
a)Cy1がイソキサゾールであり、R1、R2、R3およびR4の各々が水素であり、Qが結合手であり、およびWがp−フルオロフェニルである場合、その場合にはCy2はピリジルまたはN−ピロリジニル以外の基であり;
−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(1−メチル−1−フェニルエチル)−5−ニトロピリミジン−2,4−ジアミン;4−(4,4’−ビピペリジン−1−イル)−N−(2−クロロベンジル)−5−ニトロピリミジン−2−アミン;N2−(2−クロロベンジル)−N4−({4−[(ジメチルアミノ)メチル]シクロヘキシル}メチル)−5−ニトロピリミジン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2,5−ジフルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[4−(ジフルオロメトキシ)ベンジル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2−エトキシベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−[(1S)−1−フェニルエチル]ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2−メチルベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2−フルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(3−クロロ−2−フルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−(4−ペンチルベンジル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(4−ブトキシベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2,3−ジメトキシベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)−シクロヘキシル]メチル}−N2−(2,5−ジメトキシベンジル)−5−ニトロ− ピリミジン−2,4−ジアミン;N2−(2−クロロベンジル)−N4−[7−(ジメチルアミノ)ヘプチル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(1,1’−ビフェニル−2−イルメチル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(4−フルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2,4−ジフルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(3−フルオロ−4−メチルベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2,3−ジフルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ブロモ−N2−(2−クロロベンジル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]−メチル}−N2−(2,6−ジメトキシベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2,6−ジフルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−フルオロ−3−(トリフルオロメチル)ベンジル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(4−クロロ−2−フルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−(1−フェニルシクロプロピル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[1−(2−クロロフェニル)−1−メチルエチル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2,3−ジヒドロ−1−ベンゾフラン−5−イルメチル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[(1,5−ジメチル−1H−ピロール−2−イル)メチル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2−ブロモベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2,3−ジメチルベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2,4−ジメチルベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2,5−ジメチルベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−フルオロ−5−(トリフルオロメチル)ベンジル[−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−(メチルチオ)ベンジル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−{2−[(トリフルオロメチル)チオ]ベンジル}ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(3−フルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(6−クロロ−2−フルオロ−3−メチルベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2−クロロ−6−フルオロ−3−メチルベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−2−ナフチル−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(1−ナフチルメチル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−フルオロ−4−(トリフルオロメチル)ベンジル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(4−クロロ−2−メチルベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(5−クロロ−2−)メチルベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(3−クロロ−2−メチルベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[5−フルオロ−2−(トリフルオロメチル)ベンジル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(−5−クロロ−2−フルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2,3−ジフルオロ−4−メチルベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(5−フルオロ−2−メチルベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−1−ナフチル−5−ニトロピリミジン−2,4−ジアミン;{4−トランス−[({2−[(2−クロロベンジル)アミノ]−5−ニトロピリミジン−4−イル}アミノ)メチル]シクロヘキシル}メタノール;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ブロモ−N2−(2,5−ジクロロベンジル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ブロモ−N2−(2,4−ジクロロベンジル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ブロモ−N2−(2−ブロモベンジル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(シクロヘキシルメチル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2−ナフチルメチル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ブロモ−N2−[2−(トリフルオロメトキシ)ベンジル]ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ブロモ−N2−[2−(トリフルオロメチル)ベンジル]ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−(ジフルオロメトキシ)ベンジル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[3−(ジフルオロメトキシ)ベンジル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2−クロロ−4−フルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2−クロロ−3,6−ジフルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−(2,3,5−トリフルオロベンジル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−(2,3,4,5−テトラフルオロベンジル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−[(1R)−1−フェニルエチル]ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N
2−2,3−ジヒドロ−1H−インデン−2−イル−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[(1S)−2,3−ジヒドロ−1H−インデン−1−イル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[(1R)−2,3−ジヒドロ−1H−インデン−1−イル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(4−クロロ−1−ナフチル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(4−メトキシ−2−ナフチル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−キノリン−6−イルピリミジン−2,4−ジアミン;N4−{[4−トランス−(アミノメチル)シクロヘキシル]メチル}−N2−(2,5−ジクロロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−トランス−(アミノメチル)シクロヘキシル]メチル}−N2−(2,3−ジクロロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−(2−クロロフェニル)エチル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−(3−クロロフェニル)エチル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2−クロロ−6−フェノキシベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ブロモ−N2−2−ナフチルピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ブロモ−N2−(1−ナフチルメチル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−(ピリジン−3−イルメチル)ピリミジン−2,4−ジアミン;4−({[4−(アミノメチル)シクロヘキシル]メチル}アミノ)−2−[(2−クロロベンジル)アミノ]ピリミジン−5−カルボニトリル;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[4−(ジメチルアミノ)ベンジル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−トランス−(アミノメチル)シクロヘキシル]メチル}−N2−(2−ブロモベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−(7−アミノヘプチル)−N2−(2−ブロモベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−(7−アミノヘプチル)−N2−(2,5−ジクロロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N−({4−[({2−[(2−クロロベンジル)アミノ]−5−ニトロピリミジン−4−イル}アミノ)メチル]シクロヘキシル}メチル)グアニジン;N2−(3−アミノベンジル)−M−{[4(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−(2−ニトロベンジル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[−2−(2−ブロモフェニル)エチル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2−ブロモベンジル)−5−クロロピリミジン−2,4−ジアミン;(4−{[(2−{[2−(1H−インドール−3−イル)エチル]アミノ}−5−ニトロピリミジン−) 4−イル)アミノ]メチル}シクロヘキシル)メタンアミニウムクロリド;N−({3−[({2−[(2−クロロベンジル)− アミノ]−5−ニトロピリミジン−4−イル}アミノ)メチル]シクロヘキシル}メチル)グアニジン;3−({[4−({[4−(アミノメチル)シクロヘキシル]メチル}アミノ)−5−ニトロピリミジン−2−イル]アミノ}メチル)フェノール;(4−{[(2−{[2−(1H−イミダゾール−4−イル)エチル]アミノ}−5−ニトロピリミジン−4−イル)アミノ]メチル}シクロヘキシル)−メタンアミニウムクロリド;N2−(2−クロロベンジル)−M−({4−シス−[(ジメチルアミノ)メチル]シクロヘキシル}メチル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−クロロ−N2−(2−クロロベンジル)ピリミジン−2,4−ジアミン;N2−(2−クロロベンジル)−5−ニトロ−N4−(ピペリジン−4−イルメチル)ピリミジン−2.4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−(2−フェニルエチル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−(3−フェニルプロピル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N−2−(4−フェニルブチル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル−]メチル}−5−ニトロ−N2−(2−フェニルプロピル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−(4−メトキシフェニル)エチル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−(3−メトキシフェニル)エチル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−(2−メトキシフェニル)エチル]−5−ニトロピリミジン−2,4−ジアミン;4−[({2−[(2−クロロベンジル)アミノ]−5−ニトロピリミジン−4−イル}アミノ)メチル]ピペリジン−1−カルボキシイミダミド;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(3,5−ジクロロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−(5−アミノペンチル)−N2−(2−クロロベンジル)−5−ニトロピリミジン−2,4−ジアミン;2−(ベンジルアミノ)−4−(1,4,6,7−テトラヒドロイミダゾ[4,5−c]ピリジン−5−イル)−5−トリフルオロメチル−ピリミジン;2−(4−クロロベンジルアミノ)−4−(1,4,6,7−テトラヒドロイミダゾ[4,5−c]ピリジン−5−イル)−5−ニトロ−ピリミジン;2−(2−クロロベンジルアミノ)−4−(1,4,6,7−テトラヒドロイミダゾ[4,5−c]ピリジン−5−イル)−5−ニトロ−ピリミジン;2−(ベンジルアミノ)−4−(1,4,6,7−テトラヒドロイミダゾ[4,5−c]ピリジン−5−イル)−5−ニトロ−ピリミジン;またはN4−{[トランス−4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−[2−(トリフルオロメトキシ)ベンジル]ピリミジン−2,4−ジアミン
より選択される。
フルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2−クロロ−3,6−ジフルオロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−(2,3,5−トリフルオロベンジル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−2,3−ジヒドロ−1H−インデン−2−イル−5− ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(4−クロロ−1−ナフチル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(4−メトキシ−2−ナフチル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−キノリン−6−イルピリミジン−2,4−ジアミン;N4−{[4−トランス−(アミノメチル)シクロヘキシル]メチル}−N2−(2,3−ジクロロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−(2−クロロフェニル)エチル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−(3−クロロフェニル)エチル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ブロモ−N2−2−ナフチルピリミジン−2,4−ジアミン;4−({[4−(アミノメチル)シクロヘキシル]メチル}アミノ)−2−[(2−クロロベンジル)アミノ]ピリミジン−5−カルボニトリル;N4−{[4−トランス−(アミノメチル)シクロヘキシル]メチル}−N2−(2−ブロモベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−(7−アミノヘプチル)−N2−(2−ブロモベンジル)−5−ニトロピリミジン−2,4−ジアミン;N4−(7−アミノヘプチル)−N2−(2,5−ジクロロベンジル)−5−ニトロピリミジン−2,4−ジアミン;N−({4−[({2−[(2−クロロベンジル)アミノ]−5−ニトロピリミジン−4−イル}アミノ)メチル]シクロヘキシル}メチル)グアニジン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−(2−ニトロベンジル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−[2−(2−ブロモフェニル)エチル]−5−ニトロピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−N2−(2−ブロモベンジル)−5−クロロピリミジン−2,4−ジアミン;N−({3−[({2−[(2−クロロベンジル)アミノ]−5−ニトロピリミジン−4−イル}アミノ)メチル]シクロヘキシル}メチル)グアニジン;3−({[4−({[4−(アミノメチル)シクロヘキシル]メチル}アミノ)−5−ニトロピリミジン−2−イル]アミノ}メチル)フェノール;N2−(2−クロロベンジル)−N4−({4−シス−[(ジメチルアミノ)メチル]シクロヘキシル}メチル)−5−ニトロピリミジン−2,4−ジアミン;N2−(2−クロロベンジル)−5−ニトロ−N4−(ピペリジン−4−イルメチル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−(2−フェニルエチル)ピリミジン−2,4−ジアミン;N4−{[4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−(4−フェニルブチル)ピリミジン−2,4−ジアミン;またはN4−{[トランス−4−(アミノメチル)シクロヘキシル]メチル}−5−ニトロ−N2−[2−(トリフルオロメトキシ)−ベンジル]ピリミジン−2,4−ジアミン
より選択される。
より選択される。
R2は、以下の基:(F)CF3、(G)シアノ、(H)CONH2、(I)ハロゲン、または(J)ニトロより選択され;
R3は、以下の基:(A)水素、(B)C1−6アルキル(ハロゲンで所望により置換されてもよい)、(C)C1−6アルキルオキシ(ハロゲンで所望により置換されてもよい)、または(D)ハロゲンより選択され;
R4は、以下の基:(A)ヘテロアリール(C1−6アルキルで所望により置換されてもよい);(B)アリールまたはヘテロアリール(1または複数の以下の基:(i)C1−6アルキル(ヒドロキシル、オキソまたはNR10R11(ここでR10およびR11は、各々独立して、以下の基:(a)水素、(b)C1−6アルキル(ヒドロキシルまたはCONH2で所望により置換されてもよい)、(c)C1−6アルキルカルボニル(1または複数のハロゲンで所望により置換されてもよい)、(d)C1−6アルキルスルホニル、あるいは(e)R10とR11がメチレン架橋を構成し、それがその間にある窒素原子と一緒になって4〜6員の環を形成する基より選択される)で置換される)、(ii)CONR12R13(ここで、R12およびR13は、各々独立して、水素またはC1−6アルキルより選択される)、(iii)SO2NR12R13(ここで、R12およびR13は、各々独立して、水素またはC1−6アルキルより選択される)で置換される);(C)−NR14R15(ここで、R14およびR15は、各々独立して、(i)C1−6アルキルカルボニル(アミノで置換される)、あるいは(ii)R14とR15がメチレン架橋を構成し、それがその間にある窒素原子と一緒になって4〜7員の環を形成し、そのメチレン基の1つがC1−6アルキルで置換され、そのC1−6アルキルは、各々、ヒドロキシルまたはNR10R11(ここで、R10およびR11は上記と同意義である)で所望により置換されてもよい基より選択される);(D)−CONR16R17(ここで、R16およびR17は、各々独立して、(i)C1−6アルキル(ヒドロキシルまたはNR18R19(ここで、R18およびR19は、各々独立して、水素またはC1−6アルキルより選択されるか、あるいはR18とR19はメチレン架橋を構成し、それらの間にある窒素原子と一緒になって4ないし6員の環を形成し、そのメチレン基の1つが酸素により所望により置き換えられてもよい)で置換される);または(E)C6アルキニル(アミノ、C1−3アルキルアミノまたはジ(C1−3アルキル)アミノで所望により置換されてもよい)
より選択され;および
Aは炭素または窒素より独立して選択される]
で示される化合物、あるいは互変異性体またはその医薬的に許容される塩、溶媒和物もしくはアミノ保護誘導体である。
R2は、以下の基:(A)シアノ、または(B)ニトロより選択され;
R3は、以下の基:(A)C1−3アルキル、(B)C1−3アルキルオキシ(フッ素で所望により置換されてもよい)、または(C)ハロゲンより選択され;
R4は、以下の基:(A)アリール(1または複数の以下の基:(i)C1−3アルキル(ヒドロキシル、またはNR20R21(ここでR20およびR21は、各々独立して、以下の基:(f)水素、(g)C1−3アルキル(ヒドロキシルまたはCONH2で所望により置換されてもよい)、あるいは(h)R20とR21がメチレン架橋を構成し、それがその間にある窒素原子と一緒になって5ないし6員の環を形成する基より選択される);(ii)CONH2;(iii)SO2NH2で置換される);(B)3−ピリジル(C1−3アルキルで所望により置換されてもよく、ここで各アルキル基はアミノで所望により置換されてもよい);(C)−NR22R23(ここで、R22およびR23はメチレン架橋を構成し、それがその間にある窒素原子と一緒になって5ないし6員の環を形成し、そのメチレン基の1つがC1−3アルキルで置換され、そのC1−3アルキルは、各々、OHまたはNR20R21(ここで、R20およびR21は上記と同意義である)で所望により置換されてもよい);(D)−CONR24R25(ここで、R24およびR25は、各々独立して、(i)C1−3アルキル(C1−3アルキルアミノで置換される)より選択され;および
Aは炭素または窒素より独立して選択される、
化合物、あるいは互変異性体またはその医薬的に許容される塩、溶媒和物もしくはアミノ保護誘導体である。
で示される化合物、あるいは互変異性体、その医薬的に許容される塩、溶媒和物もしくはアミノ保護誘導体である。
で示される。
で示される化合物;およびその水和物、溶媒和物、塩、またはエステルである。
で示される化合物;互変異性体;およびその医薬的に許容される塩、溶媒和物またはアミノ保護誘導体である。
で示される基であるか;または
で示される基であるか;または
で示される残基であるか;または
で示される基であるか;あるいは
で示される基のいずれかである。
で示される化合物、およびPKC−θを選択的に阻害する、その塩、水和物およびプロドラッグである。
本発明によれば、PKC−θ機能を阻害する薬剤が、PKC−θ過剰発現細胞(例、CSCまたはCSC以外の腫瘍細胞)の(i)形成;(ii)増殖;または(iii)維持;またはPKC−θ過剰発現細胞(例、CSC)の(iv)EMT;PKC−θ過剰発現細胞(例、CSC)の(v)METを改変するための、あるいはがん(例、転移性がん)を治療または予防するための活性体として有用であると提案される。かくして、本発明によれば、PKC−θ阻害剤の化合物は、がん(転移性がんを含む)を治療または予防するのに、適切には医薬組成物の形態にて有用である。本発明は、それ自体で、悪性腫瘍、特に転移性がんの徴候を治療、予防および/または緩和するための医薬組成物であって、有効量のPKC−θ阻害剤および医薬的に許容される担体および/または希釈体を含む医薬組成物を考慮する。
がんが乳がんであるいくつかの実施態様において、乳がん(例、非乳CMC腫瘍細胞)はホルモン受容体陰性(例、エストロゲン受容体(ER)陰性および/またはプロゲステロン受容体(PR)陰性)である。
放射線療法は、DNA損傷を誘発する放射波、例えば、γ線照射、X線、UV照射、マイクロ波、電子放出、放射性同位体等を含む。療法は限局した腫瘍部位を上記される形態の放射線で照射することにより達成され得る。これらの因子はすべて、DNA、DNAの前駆体、DNAの複製および修復、染色体の集合および維持に広範囲に及ぶ損傷をもたらす可能性が極めて高い。
化学治療剤は、以下の:
の1または複数のいずれかのカテゴリーより選択され得る。
免疫療法として、例えば、インターロイキン2、インターロイキン4または顆粒球マクロファージコロニー刺激因子などのサイトカインでトランスフェクトするなどの、患者の腫瘍細胞の免疫原性を向上させるエクスビボおよびインビボでの方法、T細胞アネルギーを減少させる方法、サイトカインでトランスフェクトした樹状細胞などのトランスフェクトされた免疫細胞を用いる方法、サイトカインでトランスフェクトされた腫瘍細胞系を用いる方法、および抗イディオタイプの抗体を用いる方法が挙げられる。これらの方法は、一般に、免疫エフェクター細胞および分子を用い、腫瘍細胞を標的として破壊することに依拠する。その免疫エフェクターは、例えば、悪性腫瘍細胞の表面にあるマーカーに特異的な抗体であってもよい。抗体は単独で治療のエフェクターとして供してもよく、または細胞殺滅を実際に促進するように他の細胞を募ってもよい。抗体はまた薬物またはトキシン(化学療法剤、放射性核種、リシンA鎖、コレラトキシン、百日咳トキシン等)とコンジュゲートし、単に標的剤として供してもよい。あるいはまた、エフェクターは、悪性腫瘍細胞の標的と、直接的または間接的に相互に作用する表面分子を担持するリンパ球であってもよい。種々のエフェクター細胞として、細胞傷害性T細胞およびNK細胞が挙げられる。
がん治療法の他の例として、光療法、冷凍療法、トキシン療法またはアポトーシス促進療法が挙げられる。当業者であれば、この列挙によりがんおよび他の過形成性病変のために利用可能な治療様式の型が排除されないことが分かるであろう。
PKC経路:EMTおよびCSC
PKC経路は、種々の細胞アッセイを利用して、EMTおよびCSCと関連付けられる。第1に、PKC経路インデューサーであるPMAは、形態学的変化により観察されるように、最も大きなEMT変化を惹起し(図1AおよびB)、EMTマーカー−ラミニン−5’細胞内染色(図1B)を、そしてMCF−IM実験にて創傷治癒(移動アッセイ)(図1C)を生じさせる。第2に、PKCはMCF−IMおよび基底/転移実験において細胞質および核の両方で活性である(図1D)。第3に、PMAによるPKC経路の誘発はフローサイトメトリー(FACS)分析(図1EおよびF)、乳腺球状塊アッセイ(図1G)およびCSC−誘発性遺伝子の転写物アッセイ(図1H)およびミクロRNA(図1I)により観察されるようにCD44high/CD24low−CSC系細胞の生成をもたらす。
PKC活性の阻害がEMTおよびCSC形成を減少させる
広域スペクトルPKC経路阻害剤は、形態(図2A)、FACS(図2B&C)、乳腺球状塊アッセイ(図2D&E)およびCSC誘発性遺伝子の転写分析(図2F&G)によって示されるように、MCF−IM実験にて、および基底転移性実験(図2I、J&K)においても、EMTおよびCSC経路の阻害をもたらす。反対に、従来のPKC阻害剤であるGo6976を用いるプレインキュベーションはPMA誘発性EMT様形態変化またはCSC形成を防止しなかった(図2C&H)。
PKC−θシグナル伝達および核効果の阻害はEMTおよびCSCの除去をもたらす
PKC−θ特異ペプチド阻害剤は、形態(図3A)、FACS(図3B)および転写分析(図3C)によって示されるように、MCF−IM実験にてEMTおよびCSCを除去する。PKC−βではなく、PKC−θのノックダウンは、MCF−IM実験において、EMTおよびCSCの阻害をもたらす(図3D、E&F)。PKC−θ NLS(Nuclear Localization Signal)変異体の過剰発現はPKC−θの核への侵入を減少させ、したがってPKC−θ野生型ベクターの効果と比べて、MCF−IM実験において、EMTおよびCSC効果の減少をもたらす(図3G、HおよびI)。
核PKC−θのCSCでの誘発性遺伝子プロモータとの直接結合
クロマチン免疫沈降(ChIP)アッセイのPKC−θは、PKC−θが種々のCSC実験にてCSC誘発性遺伝子CD44のプロモータと直接結合することを示した(図4A)。PKC−θの活性形態(PKC−θホスホ)は、MCF−IM実験において、CSC誘発性遺伝子−uPARおよびCD44でクロマチンと結合し(図4B&C)、この活性形態は活性な転写マーカRNAポリメラーゼ−II(Pol II)に存在する(図4D)。PKC阻害剤およびPKC−θのノックダウンがPKC−θのCD44遺伝子プロモータとの結合の減少をもたらす。
核活性PKC−θ:浸潤性乳がんのマーカー
乳がん進行におけるPKC−θの臨床的関連が、正常な乳房組織および患者より由来の浸潤性乳がんでのPKC−θタンパク質発現を調査することにより分析された。健康な個体から由来の乳房組織と比べた場合に、ER/PR+/Her−2−のサブタイプの浸潤性がんにてPKC−θの強い細胞質発現が観察された。加えて、ER/PR+/Her−2−のサブタイプの浸潤性がんは活性なPKC−θのかすかな核染色があった(図5)。あらゆる型の乳がんが、活性なPKC−θについて弱い細胞質免疫反応性を示し、受容体の状態に関係なく有糸分裂中の乳がん細胞に見られる強い核染色を示した。
ATP競合性のPKC−θ特異的阻害剤である化合物27がMCF−IMにおいてCSC形成を妨げ、PKC−θを介するシグナル伝達がNF−κB活性の必須条件である
新規で、高い選択性のあるATP競合性のPKC−θ特異的阻害剤である化合物27(C27)(Jimenez, J.M.ら、2013. 自己免疫疾患の治療用の選択的タンパク質キナーゼCシータ(PKCシータ)阻害剤の設計および最適化(Design and optimization of selective protein kinase C theta(PKC theta) inhibitors for the treatment of autoimmune diseases) Journal of Medicinal Chemistry 56: 1799-1810)が、インビトロPKC−θ活性アッセイ(図6A)およびC27で前処理したMCF−IMより得られる核および細胞抽出物(図6BおよびC)の両方においてPKC−θ活性を除去した。C27はまた、FACS(図6C)およびCSC誘発性遺伝子の転写(図6D)で測定されるようにCSC形成を除去した。さらには、C27はp50およびp65核活性を有意に減少させ(図6EおよびF)、PKC−θも間葉状態にてNF−κBタンパク質にシグナルを伝達していることを示唆する。
細胞培養およびCSCのNCSCからの分離
接着性ヒト哺乳動物腺がんMCF−7およびMDA−MB−231細胞を、低グルコースDMEM(Gibco)中で、10%FCS、2mM L−グルタミンおよび0.1%PSN抗生物質を補足して培養した。細胞を0.65ng/mlのホルボール12−ミリスチン酸13−アセタート(PMA)(Sigma-Aldrich)で、またはng/mlのTGF−β(R&D systems)で指定される回数刺激した。ビスインドリルマレイミド−I(Calbiochem)またはPKC−θペプチド阻害剤(Calbiochem)の研究のために、MCF−7細胞を刺激する1時間前に、細胞を、各々、1μMまたは30μMの阻害剤で前処理した。MDA−MB−231細胞では、該細胞を、各々、4μMまたは30μMのビスインドリルマレイミド−IまたはPKC−θペプチド阻害剤で処理した。
MCF−7細胞の単層を滅菌処理したプラスチック製チップで傷を付けた。細胞をPBSで2回、そしてDMEMで1回洗浄した。皿上の各ウェルに参照となる符号を設け、0時点での画像を顕微鏡で撮った。細胞をPMA(0.65ng/ml)で60時間にわたって処理し、適合する領域の第2の画像を撮った。創傷した単層の両面の端部を近づけ、Photoshop CS3(Adobe Systems Inc.)を用いて重ね合わせた。
各局在化シグナル(NLS)を全長PKC−θ野生型遺伝子配列の範囲内で変異させ、上記されるようにC−末端HA−タグでpTracer−CMCベクターにフレームにてクローンさせた(Sutcliffeら、2012. Front Immunol. 3: 260)。
ヒトTaqMan(登録商標)プライマーのセット:CD44、Hs00153304、CD24、Hs00273561、uPAR、Hs00182181、ラミニン−5、Hs00194333、Zeb−1、Hs00611018、フィブロネクチン、Hs00415006およびインテグリン−β、Hs00168458(Applied Biosystems)を用いた。SYBRグリーンリアルタイムPCRに使用されるプライマーは:Zeb1(センス:5’−GTGCTGTAAGTGCCATTTCTCAGTA−3’およびアンチセンス:5’−CAAGAGACAAATCAACAAATGCTAGTT−3’)およびシクロフィリンA(センス:5’−CTCCTTTGAGCTGTTTGCAG−3’およびアンチセンス:5’−CACCACATGCTTGCCATCC−3’)である。
ヒトPKC−θsiRNA(sc−36252)、p50siRNA(sc−44211)およびp65siRNA(sc−44212)をSanta Cruz Biotechnologiesより購入し、10nM siRNAでのフォワードトランスフェクションはLipofectamine2000(Invitrogen)を用いて実施された。
全RNAはTRIzol(登録商標)試薬(Invitrogen)を用いて抽出され、cDNAの第1鎖はSuperscript(登録商標)IIIRNaseH−逆転写酵素キット(Invitrogen)を用いて合成された。TaqMan(登録商標)遺伝子発現アッセイおよびSYBRグリーンリアルタイムPCRは上記されるように実施された(Sutcliffeら、2009. Molecular and Cellular Biology. 29: 1972-86)。ミクロRNAアッセイはTaqMan(登録商標)ミクロRNA逆転写キット(ABI4366596)で行われ、データをSutcliffeら(2010、Molecular Cell. 41: 704-719)にて以前に記載されるようにRNU6Bに正規化した。
ChIPバッファーをUpstate Biotechnologyより購入し、Upstate Biotechnologyによって供給されるプロトコルに従って、以前に記載されるようにChIPアッセイを行った(Sutcliffeら、2011. Molecular Cell. 41: 704-719)。使用される抗体は:抗PKC−θ(Santa Cruz、sc−212)、抗PKC−θホスホs695(Abcam、ab76568)およびPol II c−21(Abcam、ab817)であった。RT−PCRに使用されるプロモータプライマーは、ヒトCD44(Fwd:TGAGCTCTCCCTCTTTCCAC、Rev:TTGGATATCCTGGGAGAGGA)、uPAR(Fwd:GGGAAGCAAAGCAAGGGTTA、Rev:GTTTTGTCAGGAGGGATACTGG)およびIL−6(Fwd:CTCACCCTCCAACAAAGATTT、Rev:CAGAATGAGCCTCAGACATC)であった。連続的ChIPアッセイは、Sutcliffeら(2011. Molecular Cell. 41: 704-719)によって以前に記載されるようにして行われた。
PKCをEnzo Life Sciences(DI−EKS−420A)より購入し、その活性アッセイを以前に記載されるように製造業者のプロトコルに従って行った(Sutcliffe、2012 前掲)。
免疫組織化学的検査を標準プロトコルに従ってボンド自動システム(Vision Biosystems)を用いて行った。簡単には、5μMの組織セクションをワックス除去し、グレーデッドアルコールで再水和させ、抗PKC−θまたは抗PKC−θホスホ抗体を用いて別々に染色した(0539の記載に従う)。pH8で28分間熱回復(heat retrieval)を用いた。クロモゲン・ファスト・レッド(Chromogen Fast Red)(Leica Biosystems)およびDAKOエンビジョン(Envision)キットを用いてシグナルを可視化した。ヘマトキシリン対比染色を用いて核を可視化した。各操作において、陽性および陰性のアイソタイプと適合した対照を各スライドに含め、虚偽の陽性染色のないことを保証した。
データをマイクロソフトエクセル(Microsoft)を用いて解析し、プリズム(Prism)(version 5.0、GraphPad software)を用いてグラフを作成した。
PKC−θおよびPKC−β活性アッセイ(Enzo Life Sciences;DI−EKS−420A)を、製造業者のプロトコルに従って、以前に(Sutcliffeら、2012. Chromatinized Protein Kinase C-theta: Can It Escape the Clutches of NF-kappaB? Front Immunol 3: 260)にて記載されるようにして行った。
トランスAM NF−κBファミリーキットをNF−κB活性アッセイに用いた(43296、Active Motif)。製造業者のガイドラインに従って、アッセイを行った。MDA−MB231またはMCF−IM(全細胞から由来)からのタンパク質(5μg)、核、細胞膜抽出物をこのアッセイのために三重重複して用いた。Raji核抽出物を陽性対照として用いた。野生型および変異したコンセンサスオリゴヌクレオチドも、各々、陰性および陽性対照として使用された。
イムノブロット分析を、製造業者のプロトコルに従って、以前に(Raoら、2003. c-Rel is required for chromatin remodeling across the IL-2 gene promoter. Journal of immunology 170: 3724-3731)に記載されるように、抗PKC−θ(sc−212、Santa Cruz)、抗p65(ab7970、Abcam)、抗p65ホスホ(ser−468)(3039、Cell Signaling)、抗p65ホスホ(ser−536)(3031、Cell Signaling)およびRNA Pol II(c−21)(ab817、Abcam)抗体を用いて行った。
Claims (74)
- PKC−θ過剰発現細胞の(i)形成;(ii)増殖;(iii)維持;(iv)EMT;または(v)METの少なくとも1つを改変する方法であって、PKC−θ過剰発現細胞を、形成、増殖、維持、EMTまたはMETを調節する量のPKC阻害剤と接触させることを含むか、接触させることからなるか、あるいは本質的に接触させることからなる方法。
- PKC−θ過剰発現細胞が、CSC、およびCSC以外の腫瘍細胞より選択される、請求項1に記載の方法。
- PKC−θ過剰発現細胞がCSCである、請求項1に記載の方法。
- PKC−θ過剰発現細胞がCSC以外の腫瘍細胞である、請求項1に記載の方法。
- PKC−θ過剰発現細胞を、PKC−θ過剰発現細胞の形成を阻害する量のPKC−θ阻害剤と接触させる、請求項1〜4のいずれか一項に記載の方法。
- PKC−θ過剰発現細胞を、PKC−θ過剰発現細胞の増殖を阻害する量のPKC−θ阻害剤と接触させる、請求項1〜4のいずれか一項に記載の方法。
- PKC−θ過剰発現細胞を、PKC−θ過剰発現細胞のEMTを阻害する量のPKC−θ阻害剤と接触させる、請求項1〜4のいずれか一項に記載の方法。
- PKC−θ過剰発現細胞を、PKC−θ過剰発現細胞のMETを刺激または誘発する量のPKC−θ阻害剤と接触させる、請求項1〜4のいずれか一項に記載の方法。
- CSCが乳房、前立腺、肺、膀胱、膵臓、結腸、黒色腫、肝臓または神経膠腫のCSCである、請求項2または請求項3に記載の方法。
- CSCが乳房CSCである、請求項9に記載の方法。
- 乳房CSCが乳房上皮CSCである、請求項10に記載の方法。
- 乳房上皮CSCが乳管上皮CSCである、請求項11に記載の方法。
- CSCが多能性幹細胞マーカーであるOct4またはSox2の発現を減じるかまたは抑止する、請求項2、3および9〜12のいずれか一項に記載の方法。
- CSC以外の腫瘍細胞がCSC以外の乳房、前立腺、肺、膀胱、膵臓、結腸、黒色腫、肝臓または神経膠腫腫瘍細胞である、請求項2または請求項4に記載の方法。
- CSC以外の腫瘍細胞がCSC以外の乳房腫瘍細胞である、請求項14に記載の方法。
- CSC以外の乳房腫瘍細胞がCSC以外の乳房上皮腫瘍細胞である、請求項15に記載の方法。
- CSC以外の乳房上皮腫瘍細胞がCSC以外の乳管上皮腫瘍細胞である、請求項16に記載の方法。
- CSCが、ABCB5、ALDH1、ABCG2、α6インテグリン、α2β1インテグリン、βカテニン活性、CD15、CD13、CD20、CD24、CD26、CD29、CD44、CD90、CD133、CD166、CD271、c−Met、ヘッジホッグ−Gli、ネスチン、CXCR4、LGR5、トロップ2およびノダル−アクチビンより選択される1または複数のCSCマーカーを発現する、請求項2、3または9〜13のいずれか一項に記載の方法。
- CSCが、ALDH1、CD24、CD44、CD90、CD133、ヘッジホッグ−Gli、α6インテグリンより選択される1または複数のCSCマーカーを発現する、請求項2、3または9〜13のいずれか一項に記載の方法。
- CSCがCD24およびCD44(例、CD44high、CD24low)を発現する、請求項2、3、9〜13、18または19のいずれか一項に記載の方法。
- PKC−θ阻害剤が選択的PKC−θ阻害剤である、請求項1〜20のいずれか一項に記載の方法。
- PKC−θ阻害剤が非選択的PKC−θ阻害剤である、請求項1〜20のいずれか一項に記載の方法。
- PKC−θ阻害剤が、PKC−θ遺伝子の発現を減らすか、あるいはその遺伝子の発現産物のレベルまたは機能的活性を減じる、請求項1〜22のいずれか一項に記載の方法。
- PKC−θ阻害剤が、PKC−θのリガンド結合部位の少なくとも1つの活性を減じるか、または阻止することを含め、その機能を阻害する、請求項1〜22のいずれか一項に記載の方法。
- PKC−θ過剰発現細胞をPKC−θ阻害剤と接触させる前に、PKC−θ過剰発現細胞におけるPKC−θ遺伝子の過剰発現を検出することをさらに含む、請求項1〜24のいずれか一項に記載の方法。
- PKC−θ過剰発現細胞をPKC−θ阻害剤と接触させる前に、PKC−θ過剰発現細胞の核中にあるPKC−θまたはその増加量を検出することをさらに含む、請求項1〜25のいずれか一項に記載の方法。
- PKC−θ過剰発現細胞をPKC−θ阻害剤と接触させる前に、PKC−θ過剰発現細胞中でのPKC−θとCD44またはuPARのプロモータとの結合を検出することをさらに含む、請求項1〜26のいずれか一項に記載の方法。
- PKC−θ過剰発現細胞をPKC−θ阻害剤と接触させる前に、PKC−θ過剰発現細胞中でのPKC−θとクロマチンとの結合を検出することをさらに含む、請求項1〜27のいずれか一項に記載の方法。
- PKC−θ過剰発現細胞の1または複数のCSCマーカー(例えば、請求項18〜20のいずれか一項にて定義されるマーカー)の発現を検出することをさらに含む、請求項1〜28のいずれか一項に記載の方法。
- 対象における、少なくとも1種のPKC−θ過剰発現細胞の形成、増殖または維持を阻害することにより、および/またはCSCのEMTを阻害することにより、および/またはCSCのMETを刺激または誘発することによりがんを治療または予防する方法であって、その対象にPKC−θ阻害剤を該がんの治療または予防に効果的な量で投与することを含む、方法。
- がんが転移性がんである、請求項30に記載の方法。
- 適切には、PKC−θ阻害剤を投与する前に、対象が転移性がんに罹患しているか、またはそれを発症する危険があるかを確認することをさらに含む、請求項31に記載の方法。
- 少なくとも1種のPKC−θ過剰発現細胞がCSCである、請求項30〜32のいずれか一項に記載の方法。
- 少なくとも1種のPKC−θ過剰発現細胞がCSC以外の腫瘍細胞である、請求項30〜32のいずれか一項に記載の方法。
- 少なくとも1種のPKC−θ過剰発現細胞がCSCまたはCSC以外の腫瘍細胞である、請求項30〜32のいずれか一項に記載の方法。
- 対象における、CSC以外の腫瘍細胞の増殖を阻害するか、がんの症状を治療するかまたは改善し、あるいはがんの発症または進行を退行させるかまたは阻害する、少なくとも1種の療法を該対象に共投与することをさらに含む、請求項34または請求項36に記載の方法。
- がん療法が、放射線療法、化学療法、幹細胞移植療法、および抗体療法から選択される、請求項36記載の方法。
- がんが、乳がん、前立腺がん、肺がん、膀胱がん、膵臓がん、結腸がん、黒色腫がん、肝臓がんまたは神経膠腫がんより選択される、請求項30〜37のいずれか一項に記載の方法。
- がんが乳がんである、請求項30〜37のいずれか一項に記載の方法。
- 対象においてがん(ここで該がんはCSCおよびCSC以外の腫瘍細胞を含む)を治療または予防する方法であって、該対象にPKC−θ阻害剤をCSCの形成、増殖、維持またはEMTを阻害するのに、あるいはCSCのMETを刺激または誘発するのに効果的な量で投与することを含む、方法。
- がんが転移性癌である、請求項40に記載の方法。
- PKC−θ阻害剤を投与する前に、対象がCSCおよびCSC以外の腫瘍細胞を含むがんに罹患しているか、または該がんを発症する危険があるかを確認することをさらに含む、請求項40または請求項41に記載の方法。
- がんが、乳がん、前立腺がん、肺がん、膀胱がん、膵臓がん、結腸がん、黒色腫がん、肝臓がんまたは神経膠腫がんより選択される、請求項40〜42のいずれか一項に記載の方法。
- がんが乳がんである、請求項40〜42のいずれか一項に記載の方法。
- PKC−θ阻害剤を対象に投与する前に、該対象より得られる腫瘍サンプル(CSCおよび/またはCSC以外の腫瘍細胞を含む)中のPKC−θ遺伝子の過剰発現を検出することをさらに含む、請求項40〜44のいずれか一項に記載の方法。
- PKC−θ阻害剤を対象に投与する前に、該対象より得られる腫瘍サンプル(CSCおよび/またはCSC以外の腫瘍細胞を含む)中の1または複数のCSCマーカー(例えば、請求項18〜20のいずれか一項にて定義されるマーカー)の発現を検出することをさらに含む、請求項45に記載の方法。
- 対象においてがん(ここで該がんはCSCおよびCSC以外の腫瘍細胞を含む)を治療または予防する方法であって、該対象にPKC−θ阻害剤をCSCの形成、増殖、維持またはEMTを阻害するのに、あるいはCSCのMETを刺激または誘発するのに効果的な量で、そしてCSC以外の腫瘍細胞の増殖、残存または生存能を阻害するがんの療法または薬剤を同時に投与し、それによりがんを治療または予防することを含む、方法。
- がんの療法または薬剤が、放射線療法、手術、化学療法、ホルモン除去療法、アポトーシス促進療法および免疫療法より選択される、請求項47に記載の方法。
- がんの療法または薬剤が、速やかに分裂する細胞を標的とするか、または細胞周期または細胞分裂の中断させる、請求項47または請求項48に記載の方法。
- がんが転移性がんである、請求項47に記載の方法。
- 共投与の前に、対象がCSCおよびCSC以外の腫瘍細胞を含むがんに罹患しているか、または該がんを発症する危険があるかを確認することをさらに含む、請求項47〜50のいずれか一項に記載の方法。
- がんが、乳がん、前立腺がん、肺がん、膀胱がん、膵臓がん、結腸がん、黒色腫がん、肝臓がんまたは神経膠腫がんより選択される、請求項47〜51のいずれか一項に記載の方法。
- がんが乳がんである、請求項47〜51のいずれか一項に記載の方法。
- PKC−θ阻害剤を対象に投与する前に、該対象より得られる腫瘍サンプル(CSCおよび/またはCSC以外の腫瘍細胞を含む)中のPKC−θ遺伝子の過剰発現を検出することをさらに含む、請求項47〜53のいずれか一項に記載の方法。
- CSCが乳房CSCである、請求項47〜54のいずれか一項に記載の方法。
- PKC−θ阻害剤を対象に投与する前に、CSCが1または複数のCSCマーカー(例えば、請求項18〜20のいずれか一項にて定義されるマーカー)を発現することを検出することをさらに含む、請求項47〜55のいずれか一項に記載の方法。
- PKC−θ阻害剤と、がん治療剤とが、相乗的に有効な量で投与される、請求項47〜56のいずれか一項に記載の方法。
- 対象において、PKC−θ過剰発現細胞の形成、増殖、維持またはEMTを阻害するか、PKC−θ過剰発現細胞のMETを刺激または誘発するか、あるいはPKC−θ過剰発現細胞を含むがん(例、転移性がん)を治療または予防するのに有用である薬剤を確かめるための方法であって、ここで、調製物((i)PKC−θの少なくとも1の生物学的に活性なフラグメントまたはその変異体もしくは誘導体に対応するアミノ酸配列を含ポリペプチド;または(ii)PKC−θ遺伝子の転写物またはその一部が産生可能であるヌクレオチド配列を含むポリヌクレオチド;または(iii)PKC−θ遺伝子の発現を制御し、レポータ遺伝子に作動可能に連結する遺伝的配列の少なくとも一部(例、転写因子)を含むポリヌクレオチドを含む)を試験剤と接触させ;レポータ遺伝子のポリペプチド、代謝物または代謝物の一部、あるいは発現産物のレベルおよび/または機能的活性にて、試験剤の不存在下で、正常なまたは対照となるレベルおよび/または機能的活性と比べて減少を検出することを含み、減少すれば該試験剤がPKC−θ過剰発現細胞の形成、増殖、維持またはEMTを阻害するのに、またはPKC−θ過剰発現細胞のMETを刺激または誘発するのに、あるいはがんを治療または予防するのに有用であることを示す、方法。
- PKC−θ過剰発現細胞がCSCおよびCSC以外の腫瘍細胞より選択される、請求項58に記載の方法。
- PKC−θおよびPKC−θリガンドを薬剤と接触させ、そのPKC−θとリガンドとの結合を測定することによって決定されるように、薬剤がPKC−θとPKC−θリガンドの間の結合を阻害する、請求項58または請求項59に記載の方法。
- PKC−θ過剰発現細胞の形成、増殖、維持またはEMTを阻害するか、PKC−θ過剰発現細胞のMETを刺激または誘発するか、あるいはPKC−θ過剰発現細胞を含むがん(例、転移性がん)を治療または予防するための薬剤の製造方法であって、ここで、請求項58〜60のいずれか一項にて記載されるPKC−θの機能を阻害すると思われる薬剤を試験し、その薬剤が阻害、刺激/誘発または治療/予防の試験で陽性を示すことに基づき、該薬剤を合成する、方法。
- PKC−θ過剰発現細胞がCSCおよびCSC以外の腫瘍細胞より選択される、請求項61に記載の方法。
- PKC−θ過剰発現細胞の形成、増殖、維持またはEMTを阻害するか、PKC−θ過剰発現細胞のMETを刺激または誘発するか、あるいはPKC−θ過剰発現細胞を含むがん(例、転移性がん)を治療または予防するための薬剤の効能を改善するのに、薬剤を誘導化することをさらに含み、その誘導化された薬剤が医薬的に許容される担体および/または希釈剤と一緒に処方されてもよい、請求項61または請求項62に記載の方法。
- PKC−θ過剰発現細胞の形成、増殖、維持またはEMTを阻害するか、PKC−θ過剰発現細胞のMETを刺激または誘発するか、あるいはPKC−θ過剰発現細胞(例、CSC)を含むがん(例、転移性がん)を治療または予防するためのPKC−θ阻害剤の使用。
- PKC−θ過剰発現細胞の形成、増殖、維持またはEMTを阻害するか、PKC−θ過剰発現細胞のMETを刺激または誘発するか、あるいはPKC−θ過剰発現細胞を含むがん(例、転移性がん)を治療または予防するための医薬の製造におけるPKC−θ阻害剤の使用。
- PKC−θ過剰発現細胞がCSCおよびCSC以外の腫瘍細胞より選択される、請求項65に記載の使用。
- PKC−θ阻害剤が、リポソーム、ミセル、デンドリマー、生分解性粒子、人工DNAナノ構造物、脂質をベースとするナノ粒子、および炭素または金ナノ粒子からなる群より選択されるビヒクルに含有されるか、そうでなければ一緒にアソシエートされる、請求項66に記載の使用。
- PKC−θ阻害剤が、ポリ(乳酸)(PLA)、ポリ(グリコール酸)(PGA);ポリマーポリ(乳酸−共同−グリコール酸)(PLGA);ポリ(エチレングリコール)(PEG)、およびPLA−PEGコポリマー、あるいはそれらのいずれかの組み合わせからなる群より選択されるビヒクルによって対象に投与される、請求項67に記載の使用。
- がんの療法または薬剤のがん細胞に対する生物学的効果を強化する方法であって、その必要とする対象にがん療法または薬剤と一緒に有効量のPKC−θ阻害剤を投与することを含む、方法。
- がんの療法または薬剤が化学治療薬または放射線療法である、請求項69に記載の方法。
- PKC−θ過剰発現細胞の形成、増殖、維持またはEMTを阻害するか、PKC−θ過剰発現細胞のMETを刺激または誘発するか、あるいはPKC−θ過剰発現細胞(例、CSC)を含むがん(例、転移性がん)を治療または予防するための医薬組成物であって、PKC−θ阻害剤と、CSC以外の腫瘍細胞の増殖、残存または生存能を阻害する薬剤とを含む、医薬組成物。
- CSC以外の腫瘍細胞の増殖、残存または生存能を阻害するがんの療法または薬剤の効能を強化するためのPKC−θ阻害剤の使用。
- PKC−θ阻害剤と、CSC以外の腫瘍細胞の増殖、残存または生存能を阻害するがんの療法または薬剤との、PKC−θ過剰発現細胞(例、CSC)およびCSC以外の腫瘍細胞を含むがんを治療または予防するための使用。
- PKC−θ阻害剤が、所望によりがんの療法または薬剤が、この目的のために医薬として調製または製造される、請求項73に記載の使用。
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ES2851724T3 (es) | 2021-09-08 |
JP2021006530A (ja) | 2021-01-21 |
US20160354367A1 (en) | 2016-12-08 |
WO2015039187A1 (en) | 2015-03-26 |
CA2923765C (en) | 2021-06-29 |
EP3046560A1 (en) | 2016-07-27 |
US20190192509A1 (en) | 2019-06-27 |
EP3046560A4 (en) | 2017-06-14 |
US10736892B2 (en) | 2020-08-11 |
US10124001B2 (en) | 2018-11-13 |
AU2014324092B2 (en) | 2020-02-06 |
JP6998657B2 (ja) | 2022-02-04 |
EP3046560B1 (en) | 2021-01-06 |
CA2923765A1 (en) | 2015-03-26 |
SG11201601408PA (en) | 2016-04-28 |
CN105764513A (zh) | 2016-07-13 |
AU2014324092A1 (en) | 2016-03-10 |
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