JP2010502731A - Parp阻害剤による脂肪酸合成の阻害、及びその治療方法 - Google Patents
Parp阻害剤による脂肪酸合成の阻害、及びその治療方法 Download PDFInfo
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Abstract
Description
当該出願は、2006年9月5日付けで出願された米国仮出願番号第60/842,479号の利益を主張し、上記文献の全体を本明細書中に援用する。
を含んで成る前記方法に関する。
本願明細書中で言及されたすべての刊行物及び特許出願は、それぞれの個々の刊行物又は特許出願が具体的、且つ、個別に援用されるべく示されたのと同程度に、本明細書中に援用される。
用語「アリール」は、炭素原子だけを含む、場合により置換されている単環式又は二環式芳香族環を指す。前記用語にはまた、接着点が芳香族部分にある単環式シクロアルキル又は単環式シクロヘテロアルキル基に融合したフェニル基も含まれる。アリール基の例には、例えば、フェニル、ナフチル、インダニル、インデニル、テトラヒドロナフチル、2,3-ジヒドロベンゾフラニル、ジヒドロベンゾピラニル、1,4-ベンゾジオキサニル等が含まれる。
「ニトロベンズアミド前駆体化合物」は、以下の式(Ia):
本発明で有用なPARP阻害剤(前駆体化合物)は、以下の式(Ia):
グルコースの酸化は、グルコースが乳酸又はピルビン酸のいずれかに酸化するところの解糖として知られている。好気的条件下では、ほとんどの組織における生成物はピルビン酸であるので、その経路は好気的解糖として知られている。例えば、長時間の激しい運動中のように酸素を使い果たしたとき、多くの組織において優位な糖分解生成物は乳酸であるので、その過程は嫌気的解糖として知られている。解糖の経路は、2つの別個の段階から成ると考えられる。第1段階では、2当量のATPが、グルコースからフルクトース1,6-ビスリン酸(F1,6BP)への変換のために使用される。第2段階では、4当量のATP及び2当量のNADHの産生を伴って、F1,6BPが、ピルビン酸に分解される(図1及び2を参照のこと)。
ピルビン酸+CoA+NAD+→CO2+アセチル-CoA+NADH+H+、
となる。
脂肪酸は、基質であるアセチルCoA、マロニルCoA、及びNADPHを使用する脂肪酸シンターゼ(FAS)によって合成される。これにより、脂肪酸合成経路は、通常、4つの酵素、FAS、及びその基質を産生する3つの酵素:アセチルCoAカルボキシラーゼ(ACC)、リンゴ酸酵素、及びクエン酸リアーゼを含むと考えられる。経路に基質を送り込むことができる他の酵素、例えば、ヘキソース一リン酸シャントを介してNADPHを産生する酵素などもまた、脂肪酸合成速度に影響するので、これにより、細胞において、それは内因的に合成された脂肪酸に依存する。これらの酵素の発現又は活性の阻害は、内因的に合成された脂肪酸に依存する癌細胞の増殖に影響する。
対象のサンプル中の脂肪酸のレベルの定量、又はPARP阻害剤又はその代謝産物を用いた治療後の脂肪酸合成の阻害の定量には、これだけに制限されることなく、酵素アッセイ、ガス・クロマトグラフィー/質量分析(GC/MS)などの質量分析、質量選択検出器分析(MSD)、化学イオン化及び選択モニタリング(SIM)、マス・アイソトポマー分布解析(MIDA)、高速液体クロマトグラフィー(HPLC)、又は核磁気共鳴(NMR)を含めた当該技術分野で知られている様々な検出方法が含まれる。
本発明における使用に好適な化合物は、脂肪酸合成を阻害する化合物である。好ましくは、前記阻害剤(及びその代謝産物)は、PARP阻害剤である。本明細書中に提供される化合物による脂肪酸合成の阻害は、グルコース経路又は脂肪酸生合成経路の中の1種類以上の酵素の阻害を含み得る。本発明の好ましいPARP阻害剤は、以下の式(I):
本発明における癌には、これだけに制限されることなく、結腸腺癌、食道腺癌、肝臓肝細胞癌腫、扁平上皮細胞癌、膵臓腺癌、膵島細胞腫瘍、直腸腺癌、消化管間質腫瘍、胃腺癌、副腎皮質細胞癌、濾胞癌腫、乳頭癌腫、乳癌、腺管癌、小葉癌、管内癌、粘液性癌腫、葉状腫瘍、卵巣腺癌、子宮内膜腺癌、顆粒膜細胞腫瘍、粘膜性嚢胞腺癌、子宮頚部腺癌、外陰部扁平上皮細胞癌、基底細胞腺癌、前立腺腺癌、骨巨細胞腫、骨肉腫、喉頭癌、肺腺癌、腎癌、膀胱癌、ウィルムス腫瘍、及びリンパ腫が含まれる。
1つの態様において、本発明は、PARP阻害剤の有効量を投与することによるHer-2関連癌の治療方法を提供する。Her-2疾患は、一種の乳癌である。攻撃的な増殖と予後不良を特徴とし、腫瘍細胞における、過剰な数のHER2(ヒト上皮成長因子受容体-2)と呼ばれる遺伝子の存在に起因する。本明細書中に開示されるPARP阻害剤と組み合わせて使用され得る治療法は、これだけに制限されることなく、例えば、ハーセプチンなどのHer-2抗体、抗ホルモン(例えば、選択的エストロゲン受容体モジュレーター(SERM)であるタモキシフェン)、化学療法や放射線療法、アロマターゼ阻害剤(例えば、アナストロゾール、レトロゾール、及びエキセメスタン)、並びに抗エストロゲン剤(例えば、フルバスタチン(Faslodex))が含まれる。
1つの態様において、本発明は、これだけに制限されることなく、乳腺内の管組織における腺管癌を含めた乳癌の治療方法を提供する。
もう1つの態様において、本発明は、これだけに制限されることなく、上皮性卵巣腫瘍、卵巣の腺癌、及び卵巣から腹腔内に移動した腺癌を含めた卵巣癌の治療方法を提供する。本発明のPARP阻害剤と組み合わせて使用される卵巣癌に関する治療には、これだけに制限されることなく、外科手術、免疫療法、化学療法、ホルモン療法、放射線照射療法、又はその組み合わせが含まれる。いくつかの可能な外科的処置には、デバルキング、及び片側だけ又は両側の卵巣切除術、及び/又は片側だけ又は両側の卵管切除術が含まれる。
もう1つの態様において、本発明は、これだけに制限されることなく、子宮頚部上皮における腺癌を含めた子宮頚癌の治療方法を提供する。この癌の2つの主要なタイプ:扁平上皮細胞癌と腺癌、が存在する。一部の子宮頚癌は、これらの両方の特徴を有し、そして、腺扁平上皮癌腫又は混合性癌腫と呼ばれる。
もう1つの態様において、本発明は、これだけに制限されることなく、腺癌又は骨に移動した腺癌を含めた前立腺癌の治療方法を提供する。前立腺癌は、尿道の最初の部分を取り囲む、男性の前立腺臓器において発現する。
もう1つの態様において、本発明は、これだけに制限されることなく、膵管組織における類上皮癌腫、及び膵管における腺癌を含めた膵臓癌の治療方法を提供する。
もう1つの態様において、本発明は、これだけに制限されることなく、膀胱の移行細胞癌を含めた膀胱癌の治療方法を提供する。膀胱癌は、尿路上皮癌(移行細胞癌)又は膀胱を内張りする尿路上皮細胞の腫瘍である。膀胱癌の残りの症例は、扁平上皮細胞癌と、腺癌と、小細胞癌である。それらが非侵襲性であるか又は侵襲性であるか、及びそれらが乳頭状であるか又は扁平であるかよって、いくつかの尿路上皮癌のサブタイプが存在する。非侵襲性の腫瘍が膀胱の最内層である尿管上皮に存在するのに対して、浸潤癌は尿管上皮から膀胱の主たる筋壁の深層まで広がった。侵襲性の乳頭状尿路上皮癌は、膀胱の中空に分岐し、且つ、膀胱壁内に外側にも増殖する細長い指のような突起である。非侵襲性の乳頭状尿路上皮腫瘍は、膀胱の中心に向かって増殖する。非侵襲性の扁平尿路上皮腫瘍(別名、扁平上皮内癌)が、膀胱の内面の空洞部分に最も近い細胞層に限定されるのに対して、侵襲性の扁平尿路上皮癌は、膀胱の深層、特に筋層に浸潤する。
もう1つの態様において、本発明は、急性骨髄性白血病(AML)、好ましくは末梢血の急性前骨髄性白血病の治療方法を提供する。AMLは骨髄で始まるが、例えば、リンパ節、肝臓、脾臓、中枢神経系、及び精巣を含めた身体の他の部分に拡散する可能性がある。AMLは、複製され、そして、蓄積し続ける、通常、顆粒球か単球である未成熟な骨髄細胞を特徴とする。
もう1つの態様において、本発明は肺癌の治療方法を提供する。肺癌の一般的なタイプは、扁平上皮細胞癌、腺癌、及び大細胞未分化癌に分類される非小細胞肺癌(NSCLC)である。本発明のPARP阻害剤と組み合わせた肺癌のための治療の選択肢には、外科手術、免疫療法、放射線照射療法、化学療法、光力学療法、又はその組み合わせが含まれる。肺癌の治療のためのいくつかの可能な外科的な選択肢は、区域若しくは楔状切除、葉切除術、又は一側肺全摘術である。放射線治療は、外照射療法又は小線源療法である。
もう1つの態様において、本発明は、皮膚癌の治療方法を提供する。皮膚で始まる数タイプの癌が存在する。最も一般的なタイプは、非黒色腫皮膚癌である基底細胞腺癌と扁平上皮細胞癌である。光線性角化症は、時々、扁平上皮細胞癌になる肌の状態である。非黒色腫皮膚癌は、身体の他の部分にめったに拡散しない。皮膚癌の最も稀な形態である黒色腫は、近くの組織に侵入して、身体の他の部分に拡散する傾向がより強い。
もう1つの態様において、本発明は、眼の網膜芽細胞腫の治療方法を提供する。網膜芽細胞腫は網膜の悪性腫瘍である。腫瘍は、片眼だけに、又は両眼にある可能性がある。本発明のPARP阻害剤と組み合わせて使用される治療の選択肢には、摘出(眼を取り出す手術)、放射線照射療法、凍結療法、光凝固、免疫療法、温熱療法、及び化学療法が含まれる。放射線治療は、外照射療法又は小線源療法であり得る。
もう1つの態様において、本発明は、眼内(眼)黒色腫の治療方法を提供する。眼球内黒色腫は、癌細胞が葡萄膜と呼ばれる眼の部分に見つかる疾患である。葡萄膜には、虹彩、毛様体、及び脈絡膜が含まれる。眼球内黒色腫は、ほとんどの場合、中年の人で起こる。本発明のPARP阻害剤と組み合わせて使用される治療には、外科手術、免疫療法、放射線照射療法、及びレーザー療法が含まれる。外科手術は、眼球内黒色腫の最も一般的な治療である。いくつかの可能な外科的な選択肢は、虹彩切除、虹彩線維柱帯切除(iridotrabeculectomy)、虹彩毛様体切除、脈絡膜切除(choroidectomy)、摘出、及び眼窩内容除去である。放射線治療は、外照射療法又は小線源療法であり得る。レーザー治療は、腫瘍を破壊する非常に強力な光線、温熱療法、又は光凝固であり得る。
もう1つの態様において、本発明は、子宮内膜癌の治療方法を提供する。子宮内膜癌は、子宮の内側の内壁である子宮内膜で始まる癌である。子宮及び子宮内膜の癌の例のいくつかには、これだけに制限されることなく、腺癌、腺類癌、腺扁平細胞癌、乳頭状漿液性腺癌、明細胞腺癌、子宮肉腫、間質性肉腫、悪性中胚葉性混合腫瘍、及び平滑筋肉腫が含まれる。
もう1つの態様において、本発明は、原発性肝癌(肝臓で始まる癌)の治療方法を提供する。原発性肝癌は、成人と子供の両方に起こり得る。本発明のPARP阻害剤と組み合わせて使用され得る異なったタイプの治療は、外科手術、免疫療法、放射線照射療法、化学療法、及び経皮的エタノール注入法が含まれる。使用され得る外科手術のタイプは、凍結外科手術、部分肝切除、肝臓全摘出、及び高周波アブレーションである。放射線治療は、外照射療法、小線源療法、放射線増感剤、又は放射標識抗体であり得る。他のタイプの治療には、温熱療法と免疫療法が含まれる。
もう1つの態様において、本発明は、腎癌の治療方法を提供する。腎癌(別名、腎細胞癌又は腎臓腺癌)は、悪性細胞が腎臓で細管の内壁で見つかる疾患である。本発明のPARP阻害剤と組み合わせて使用され得る治療には、外科手術、放射線照射療法、化学療法、及び免疫療法が含まれる。腎癌を治療するいくつかの可能な外科的な選択肢は、部分腎摘出、単純腎切除、及び根治的腎摘出である。放射線治療は、外照射療法又は小線源療法であり得る。幹細胞移植が、腎癌を治療するために使用され得る。
もう1つの態様において、本発明は、甲状腺癌の治療方法を提供する。甲状腺癌は、癌(悪性)細胞が甲状腺の組織で見つかる疾患である。甲状腺癌の4つの主たるタイプは、乳頭癌、濾胞性癌、髄様癌、及び未分化癌である。甲状腺癌は、外科手術、免疫療法、放射線照射療法、ホルモン療法、及び化学療法によって治療され得る。本発明のPARP阻害剤と組み合わせて使用され得るいくつかの可能な外科的な選択肢は、これだけに制限されることなく、葉切除術、甲状腺全摘、甲状腺摘出、及びリンパ節切除が含まれる。放射線療法は、体外照射療法であり得るか、又は放射性ヨウ素が含まれる液体の摂取が求められる可能性がある。ホルモン療法は、癌細胞が成長するのを止めるホルモンを使用する。甲状腺癌を治療する際に、ホルモンは、体が癌細胞を増殖させるかもしれない他のホルモンを作るのを止めるために使用され得る。
AIDS関連リンパ腫
もう1つの態様において、本発明は、AIDS関連リンパ腫の治療方法を提供する。AEDS関連リンパ腫は、悪性細胞が後天性免疫不全症候群(AIDS)に罹った患者のリンパ系で形成される疾患である。AIDSは、体の免疫系を攻撃し、そして、弱めるところのヒト免疫不全ウィルス(HIV)によって引き起こされる。免疫系は、その後、体に侵入する感染症及び疾患と戦うことができない。HIV疾患の人々には、感染症、リンパ腫、及び他のタイプの癌を発現する高い危険性がある。リンパ腫は、リンパ系の白血球に影響する癌である。リンパ腫は、2つの一般的なタイプ:ホジキンリンパ腫と非ホジキンリンパ腫、に分類される。ホジキンリンパ腫と非ホジキンリンパ腫の両方がAIDS患者に起こり得るが、非ホジキンリンパ腫がより一般的である。AIDS保菌者が非ホジキンリンパ腫に罹っていると、それはAIDS関連リンパ腫と呼ばれる。非ホジキンリンパ腫は、緩慢性(増殖遅延型)又は侵攻性(急速増殖型)であり得る。AIDS関連のリンパ腫は、通常、侵攻性である。AIDS関連リンパ腫の3つの主要なタイプは、びまん性大細胞型B細胞リンパ腫、B細胞免疫芽球性リンパ腫、及び小型非開裂細胞性リンパ腫である。
1つの態様において、本発明は、カポジ肉腫の治療方法を提供する。カポジ肉腫は、癌細胞が、皮膚、又は口、鼻、及び肛門を内張りする粘膜の下の組織で見つかる疾患である。カポジ肉腫は、免疫阻害剤を服用した人々において起こり得る。後天性免疫不全症候群(AIDS)に罹った患者のカポジ肉腫は、流行性カポジ肉腫と呼ばれる。カポジ肉腫は、外科手術、化学療法、放射線照射療法、及び免疫療法によって治療され得る。体外照射療法が、カポジ肉腫の一般的な治療である。本発明のPARP阻害剤と組み合わせて使用され得る治療には、これだけに制限されることなく、局所切除、電気乾燥法や掻爬、及び凍結療法が含まれる。
もう1つの態様において、本発明は、ウイルス誘発性癌の治療方法を提供する。主要なウイルス‐悪性腫瘍系には、B型肝炎ウイルス(HBV)、C型肝炎ウイルス(HCV)、及び肝細胞癌腫;ヒト・リンパ球向性ウイルス1型(HTLV-1)及び成人T細胞白血病/リンパ腫;及びヒト乳頭腫ウイルス(HPV)や子宮頚癌が含まれる。
HBVとHCV、及び肝細胞癌腫又は肝臓癌は、細胞死とその後の再生を引き起こすことによって肝臓における慢性的な複製によって作動するように見える。本発明のPARP阻害剤と組み合わせて使用され得る治療には、これだけに制限されることなく、外科手術、免疫療法、放射線照射療法、化学療法、及び経皮的エタノール注入法が含まれる。使用できる外科手術のタイプは、凍結外科手術、部分肝切除、肝臓全摘出、及び高周波アブレーションである。放射線治療は、外照射療法、小線源療法、放射線増感剤、又は放射標識抗体であり得る。他のタイプの治療には、温熱療法と免疫療法が含まれる。
成人T細胞性白血病は、血液と骨髄の癌である。本発明のPARP阻害剤と組み合わせて使用され得る成人T細胞性白血病/リンパ腫の治療には、これだけに制限されることなく、放射線照射療法、免疫療法、及び化学療法が含まれる。放射線治療は、外照射療法又は小線源療法であり得る。成人T細胞性白血病/リンパ腫を治療する他の方法には、免疫療法、及び幹細胞移植を伴った高投与量化学療法が含まれる。
ヒト乳頭腫ウイルス(HPV)の子宮頚部への感染は、子宮頚癌の原因である。本発明のPARP阻害剤を組み合わせて使用され得る子宮頚癌の治療には、これだけに制限されることなく、外科手術、免疫療法、放射線照射療法、及び化学療法が含まれる。使用され得る外科手術のタイプは、円錐切除、子宮全摘出、両側卵管卵巣摘出、広汎性子宮全摘出、骨盤内容除去、凍結外科手術、レーザー手術、及び電気外科的ループ切除法である。放射線治療は、外照射療法又は小線源療法であり得る。
脳及び脊髄腫瘍は、頭蓋骨、又は中枢神経系(CNS)の主な構成要素である骨性脊柱に見られる組織の異常増殖である。良性腫瘍は、非癌性であり、そして、悪性腫瘍は癌腫である。脳又は脊髄で起こる腫瘍は、原発腫瘍と呼ばれる。原発腫瘍は、特定の遺伝的疾患(例えば、神経線維腫症、結節性硬化症)から、又は放射線照射若しくは発癌性化学物質への暴露から生じ得る。
星状細胞腫瘍、例えば、星状細胞腫など;未分化(悪性)星状細胞腫、例えば、大脳半球、間脳、眼、脳幹、小脳などのもの;多形膠芽腫;毛様細胞性星状細胞腫、例えば、大脳半球、間脳、眼、脳幹、小脳などのもの;上衣下巨細胞性星状細胞腫;及び多形性黄色星状膠細胞腫。乏突起膠腫、例えば、腫瘍乏突起神経膠腫など;及び未分化(悪性)乏突起神経膠腫。上衣細胞腫瘍、例えば、上衣腫など;未分化上衣腫;粘液乳頭型脳室上衣腫;及び上衣下細胞腫。混合膠腫、例えば、混合乏突起星細胞腫など;未分化(悪性)乏突起星細胞腫;及び他のもの(例えば、上衣‐星状細胞腫(ependymo-astrocytomas))。不確実な起源の神経上皮腫瘍、例えば、極性海綿芽細胞腫;星状芽細胞腫;及び大脳神経膠腫症など。脈絡叢の腫瘍、例えば、脈絡叢乳頭腫;及び脈絡叢癌(未分化脈絡叢乳頭腫)など。ニューロン性及び混合性ニューロン性神経膠腫、例えば、神経節細胞腫;小脳の形成異常の神経節細胞腫(レルミット‐デュクロ);神経節膠腫;未分化(悪性)神経節膠腫;線維形成性乳児神経節膠腫、例えば、線維形成性乳児性星状細胞腫;中枢神経細胞腫;胚芽異形成性神経上皮腫瘍;臭覚性神経芽細胞腫;神経上皮腫など。松果体実質腫瘍、例えば、松果体細胞腫;松果体芽腫;及び混合性松果体細胞腫/松果体芽腫など。神経芽細胞又は膠芽細胞要素(胚芽腫)を有する腫瘍、例えば、髄様上皮腫など;多分化能分化を有する原始神経外胚葉腫瘍、例えば、髄芽腫;脳の原始神経外胚葉腫瘍;神経芽細胞腫;網膜芽細胞腫;及び脳室上衣芽腫など。
トルコ鞍部の腫瘍、例えば、脳下垂体腺腫;下垂体癌;及び頭蓋咽頭腫など。造血器腫瘍、例えば、原発性悪性リンパ腫;形質細胞腫;及び顆粒球性肉腫など。胚細胞腫瘍、例えば、胚細胞腫;胚性癌腫;卵黄嚢腫瘍(内胚葉性洞腫瘍);絨毛癌;奇形腫;及び混合性胚細胞腫瘍など。髄膜の腫瘍、例えば、髄膜腫;異型髄膜腫;及び未分化(悪性)髄膜腫など。髄膜の非髄膜上皮性腫瘍、例えば、良性間葉;悪性間葉;一次メラノサイト病巣;造血系新生物;及び血管芽腫などの不確実な組織形成の腫瘍(毛細血管芽腫)など。脳及び脊髄神経の腫瘍、例えば、シュワン腫(神経線維腫症、神経鞘腫);神経線維腫;例えば、類上皮、分岐間葉若しくは上皮分化、及び黒色性などの悪性末梢神経鞘腫(悪性シュワン腫)など。局所腫瘍からの局所的な伸展;例えば、傍神経節腫(ケモデクトーマ);脊索腫;軟骨腫;軟骨肉腫;及び癌腫など。転移腫瘍、分類不能な腫瘍、並びに包嚢及び腫瘍様病変、例えば、ラトケ嚢腫;類上皮腫;類皮腫;第3脳室のコロイド嚢胞;腸性嚢胞;神経膠包嚢;顆粒細胞腫(分離腫、下垂体細胞腫);視床下部ニューロン性過誤腫;鼻腔内異所性膠細胞);及び形質細胞肉芽腫など。
末梢神経系は、脳と脊髄から枝分かれした神経から成る。これらの神経は、CNSと身体部分の間の通信網を形成する。末梢神経系は、体性神経系と不随意神経系にさらに細分される。体性神経系は、皮膚と筋に向かう神経から成り、意識的な活性に関与する。不随意神経系は、心臓、胃、腸などの内臓とCNSを接続する神経から成る。それは無意識の活性を媒介する。
口腔の癌には、これだけに制限されることなく、下咽頭癌、喉頭癌、上咽頭癌、及び中咽頭癌が含まれる。
胃癌の3つの主要なタイプ:リンパ腫、胃間質腫瘍、及びカルチノイド腫瘍が存在する。リンパ腫は、胃壁で見つかることもある免疫系組織の癌である。胃間質腫瘍は、胃壁の組織から発達する。カルチノイド腫瘍は、胃のホルモン産生細胞の腫瘍である。
精巣癌は、通常、若年男性の片方の又は両方の精巣で発現する癌である。精巣の癌は、生殖細胞として知られている特定の細胞において発現する。男性に起こる2タイプの胚細胞腫(GCTs)は、精上皮腫(60%)と非精上皮腫(40%)である。腫瘍はまた、精巣の支持組織及びホルモン産生組織、又は間質において生じ得る。そのような腫瘍は、生殖腺間質腫として知られている。2つのタイプは、ライディッヒ細胞腫とセルトーリ細胞腫である。二次精巣腫瘍は、別の臓器で始まり、次に精巣に拡散したものである。リンパ腫は、二次精巣癌である。
胸腺は、あなたの胸の上/前部に位置し、喉の基底部から心臓の前まで広がる小さな臓器である。胸腺には、2つの主要な細胞型、胸腺上皮細胞及びリンパ球が含まれる。胸腺上皮細胞は、胸線腫と胸腺癌の起源となる。リンパ球は、胸腺又はリンパ節にかかわらず、悪性になって、そして、ホジキン病と非ホジキンリンパ腫と呼ばれる癌を発現する可能性がある。胸腺癌には、通常、特定のホルモンを放出する、クルチツキー細胞又は神経内分泌細胞が含まれる。これらの細胞は、カルチノイド又はカルチノイド腫瘍と呼ばれる癌を生じ得る。
栄養障害及び代謝障害の例には、これだけに制限されることなく、尿崩症、ファブリ病、脂肪酸代謝障害、乳糖血症、ゴーシェ病、グルコース-6-リン酸デヒドロゲナーゼ(G6PD)、グルタル酸尿症、ハーラー症候群(hurler)、ハーラ‐シャイエ症候群、ハンター舌炎、低リン酸血症、I細胞(I-cell)、クラッベ病、乳酸アシドーシス、長鎖3-ヒドロキシアシルCoAデヒドロゲナーゼ欠損(LCHAD)、リソソーム蓄積症、マンノシドーシス、メイプルシロップ尿、マロトー‐ラミー症候群、異染色性白質萎縮症、ミトコンドリア異常、モルキオ症候群、ムコ多糖体症、神経‐代謝異常、ニーマン・ピック病、有機酸血症、プリン、フェニルケトン尿症(PKU)、ポンペ病、偽ハーラー症候群、ピルビン酸デヒドロゲナーゼ欠損、サンドホフ病、サンフィリポ症候群、シャイエ症候群、スライ症候群、テイ‐サック病、トリメチルアミン尿症(魚臭症候群)、尿素サイクル疾患、ビタミンD欠乏くる病、筋の代謝性疾患、遺伝性代謝障害、酸‐塩基平衡障害、酸中毒、アルカローシス、アルカプトン尿、α-マンノシドーシス、アミロイドーシス、貧血、鉄欠乏、アスコルビン酸欠乏、アビタミノーシス、脚気、ビオチニダーゼ欠損、糖タンパク質欠乏症候群、カルニチン障害、シスチン蓄積症、シスチン尿、ファブリ病、脂肪酸酸化障害、フコース症、乳糖血症、ゴーシェ病、ギルバート病、グルコースリン酸デヒドロゲナーゼ欠損、グルタル酸血症、糖原症、ハートナップ病、血色素症、血鉄症、肝レンズ核変性症、ヒスチジン血症、ホモシスチン尿症、高ビリルビン血症、高カルシウム血症、高インスリン症、高カリウム血症、高脂血症、シュウ酸過剰尿症、高ビタミンA症、低カルシウム血症、低血糖、低カリウム血症、低ナトリウム血症、低リン酸血症、インスリン抵抗性、ヨウ素欠乏、鉄過剰症、黄疸、慢性特発性障害、リー疾患、レッシュ‐ナイハン症候群、ロイシン代謝障害、リソソーム蓄積症、マグネシウム欠乏、メイプルシロップ尿症、MELAS症候群、メンケス縮毛症候群、代謝症候群X、ムコリピドーシス、ムコ多糖症、ニーマン-ピック病、肥満、オルニチンカルバモイルトランスフェラーゼ欠損症、骨軟化症、ペラグラ、ペルオキシソーム病、ポルフィリア、赤血球新生、斑岩、早老症、偽ゴーシェ病、レフサム病、ライ症候群、くる病、サンドホフ病、タンジアー疾患、テイ‐サックス病、テトラヒドロビオプテリン欠損、トリメチルアミン尿(魚臭症候群)、チロシン血症、尿素サイクル異常症、水‐電解質平衡異常、ウェルニッケ脳症、ビタミンA欠乏症、ビタミンB12欠乏症、ビタミンB欠乏症、ウォルマン病、及びツェルウェガー症候群が含まれる。
本発明における使用に好適な化合物は、脂肪酸合成を阻害する化合物である。好ましくは、前記阻害剤は、PARP阻害剤である。PARP阻害剤の有効量を用いた治療の前、及び/又は後の脂肪酸レベルの分析は、様々な治療上の、及び診断上の適用があった。臨床適用には、例えば、疾患の検出、予後の情報を提供するための病状の識別、例えば、PARP阻害剤の有効量を用いた治療などの治療法の選択、治療反応の予測、疾患の病期診断、病気の経過の同定、PARP阻害剤を用いた治療法の有効性の予測、(例えば、疾患発症前の)患者軌跡の観察、PARP阻害剤に対する拒絶反応の予測、治療法に関連する有効性と毒性の観察、及び再発の検出が含まれる。対象の脂肪酸レベルの識別もまた、治療法の選択、及びPARP阻害剤による治療用の対象のための用量レジメンの個別化のために使用され得る。
本発明によって提供された方法は、他の治療法と組み合わせて、本明細書中に提供される阻害剤の有効量の投与を含んで成ることができる。本発明の組成物と同時投与され得る治療の選択は、1つには、治療される病態次第であるだろう。例えば、急性骨髄性白血病を治療するために、本発明のいくつかの実施態様の化合物は、放射線照射療法、モノクローナル抗体療法、化学療法、骨髄移植、又はその組み合わせ、と組み合わせて使用され得る。
目標:この研究は、グルコースの唯一の供給源として[1,2-13C2]D-グルコースを使用して、培養OVCAR-3細胞とHeLa細胞の代謝フラックスに対する3-ニトロ-4-ヨードベンズアミド(式(III)によって表される化合物)の試験管内における効果を分析することに関する。前記分析には、細胞成長修飾効果とフラックスを相関させるステップ、抗増殖作用の作用機序を分析するステップ、並びに潜在的な毒性、選択性、及び有効性を分析するステップが含まれる。標的代謝産物には、グルコース(培地とペレットのグリコーゲン)、乳酸(培地)、13CO2(培地)、C:14(ミリスチン酸);C:16(パルミチン酸);C:18(ステアリン酸);C:18-1(オレイン酸);C:20;C:22;C:24(細胞ペレット)、脂肪酸に関するアセチル-CoA合成(細胞ペレット)、並びにRNAリボース及びDNAデオキシリボース(細胞ペレット)が含まれる。標的フラックスには、培地からのグルコース摂取;グルコースからの乳酸産生(嫌気的解糖);TCAサイクルを介したグルコースからの13CO2の放出;グリコーゲン合成;デノボ脂肪酸合成、伸長、不飽和化、及びアセチルCoA合成;並びに酸化及び非酸化反応を介したペントース・サイクル‐RNA及びDNAリボース合成が含まれる。
Claims (96)
- PARP阻害剤又はその代謝産物の有効量を、それを必要としている患者に投与して、脂肪酸合成を阻害することを含んで成る脂肪酸合成関連疾病の治療方法であって、ここで、上述の脂肪酸合成関連疾病が、肥満、糖尿病、又は心臓血管疾患である前記治療方法。
- 前記の脂肪酸が、中鎖脂肪酸又は長鎖脂肪酸である、請求項1に記載の方法。
- 前記の脂肪酸合成の阻害が、グルコース経路の中の少なくとも1種類の酵素を阻害することを含んで成る、請求項1に記載の方法。
- 前記の脂肪酸合成の阻害が、脂肪酸生合成経路の中の少なくとも1種類の酵素を阻害するステップを含んで成る、請求項1に記載の方法。
- 前記の脂肪酸合成の阻害が、アセチルCo-A、マロニルCo-A、アセチルCo-Aカルボキシラーゼ、及び脂肪酸シンターゼから成る群から選択される少なくとも1種類の酵素を阻害するステップを含んで成る、請求項1に記載の方法。
- 前記の脂肪酸合成の阻害が、脂肪酸シンターゼの中の少なくとも1種類の酵素を阻害するステップを含んで成る、請求項1に記載の方法。
- 前記の脂肪酸シンターゼが、アシルキャリアタンパク質、アセチル・トランスフェラーゼ、マロニル・トランスフェラーゼ、3-ケト-アシル-ACPシンターゼ、3-ケトアシル-ACPレダクターゼ、3-ヒドロキシ-アシル-ACPデヒドラターゼ、及びエノイル-ACPレダクターゼを含んで成る、請求項6に記載の方法。
- 前記の脂肪酸合成の阻害が、グルコースからのアセチル-CoAの合成を阻害するステップを含んで成る、請求項1に記載の方法。
- 前記の脂肪酸合成の阻害が、アセチル-CoAからの前記の脂肪酸合成を阻害するステップを含んで成る、請求項1に記載の方法。
- 前記の阻害が、グルコース経路又は脂肪酸生合成経路の代謝産物又は分子フラックスを分析することによって測定される、請求項1に記載の方法。
- 前記の代謝産物が、グルコース、グリコーゲン、乳酸、CO2、脂肪酸、アセチルCo-A、RNAリボース、及びDNAデオキシリボースから成る群から選択される、請求項10に記載の方法。
- 前記の代謝産物が、前記の分析のために化学的に誘導体化される、請求項11に記載の方法。
- 前記の分析が、質量分析法を含んで成る、請求項12に記載の方法。
- 前記の質量分析法が、マス・アイソトポマー分布解析である、請求項13に記載の方法。
- 前記のPARP阻害剤又はその代謝産物が、以下の式(II):
- 前記の治療が、経口投与、経粘膜投与、口腔内投与、鼻腔内投与、吸入法、非経口投与、静脈内、皮下、筋肉内、舌下、及び経皮投与、並びに直腸投与から成る群から選択される、請求項1に記載の方法。
- 以下のステップ:(i)PARP阻害剤又はその代謝産物の有効量を患者に投与して、脂肪酸合成を阻害し;(ii)上述の患者からの最初と2番目のサンプル中の最初と2番目の脂肪酸レベルを比較するが、ここで、上述の最初のレベル及び上述の最初のサンプルを、上述のPARP阻害剤又はその代謝産物の投与前に入手し、そして、上述の2番目のレベル及び上述の2番目のサンプルを、上述のPARP阻害剤又はその代謝産物の投与後に入手し;そして(iii)上述の比較に基づいて、上述の患者の疾患の治療における上述のPARP阻害剤又はその代謝産物の治療有効性を決定する、を含んで成る、疾患の治療におけるPARP阻害剤又はその代謝産物の治療有効性をモニターする方法。
- 前記の脂肪酸合成の阻害が、グルコース経路又は脂肪酸生合成経路の中の少なくとも1種類の酵素を阻害するステップを含んで成る、請求項19に記載の方法。
- 前記の2番目のサンプル中の前記の2番目の脂肪酸レベルが、前記の最初のサンプル中の前記の最初の脂肪酸レベルに比べて低ければ、前記のPARP阻害剤又はその代謝産物が治療的に有効である、請求項19に記載の方法。
- 前記の2番目のサンプル中の前記の2番目の脂肪酸レベルが、前記の最初のサンプル中の前記の最初の脂肪酸レベルと比べて高ければ、前記のPARP阻害剤又はその代謝産物が治療的に無効である、請求項19に記載の方法。
- 前記の最初の脂肪酸レベルと前記の2番目の脂肪酸レベルが、アッセイ技術によって測定される、請求項19に記載の方法。
- 前記の最初の脂肪酸レベルと前記の2番目の脂肪酸レベルが、質量分析法によって測定される、請求項19に記載の方法。
- 前記の質量分析法が、マス・アイソトポマー分布解析である、請求項24に記載の方法。
- 前記のPARP阻害剤又はその代謝産物が、以下の式(II):
- 前記の疾患が、癌、心臓血管、糖尿病、又は肥満である、請求項19に記載の方法。
- 前記の投与が、経口投与、経粘膜投与、口腔内投与、鼻腔内投与、吸入法、非経口投与、静脈内、皮下、筋肉内、舌下、及び経皮投与、並びに直腸投与から成る群から選択される、請求項19に記載の方法。
- 前記の最初のサンプル中の前記の最初の脂肪酸レベルが、前記の患者の病歴から決定される、請求項19に記載の方法。
- 脂肪酸合成を阻害するところのPARP阻害剤又はその代謝産物の有効量を、それを必要としている患者に投与するステップを含んで成る、Her-2関連癌の治療方法。
- 前記の脂肪酸合成の阻害が、グルコース経路又は脂肪酸生合成経路の中の少なくとも1種類の酵素を阻害するステップを含んで成る、請求項32に記載の方法。
- 前記の脂肪酸合成の阻害が、脂肪酸シンターゼの中の少なくとも1種類の酵素を阻害するステップを含んで成って、ここで、上述の酵素が、アシルキャリアタンパク質、アセチル・トランスフェラーゼ、マロニル・トランスフェラーゼ、3-ケト-アシル-ACPシンターゼ、3-ケトアシル-ACPレダクターゼ、3-ヒドロキシ-アシル-ACPデヒドラターゼ、及びエノイル-ACPレダクターゼから成る群から選択される、請求項32に記載の方法。
- 前記のPARP阻害剤又はその代謝産物が、以下の式(II):
- 前記の治療が、経口投与、経粘膜投与、口腔内投与、鼻腔内投与、吸入法、非経口投与、静脈内、皮下、筋肉内、舌下、及び経皮投与、並びに直腸投与から成る群から選択される、請求項32に記載の方法。
- Her-2抗体を投与するステップをさらに含んで成る、請求項32に記載の方法。
- 外科手術、放射線照射療法、化学療法、遺伝子治療、免疫療法、又はその組み合わせをさらに含んで成る、請求項32に記載の方法。
- 以下のステップ:
以下の式(II):
ここで、上述の式(II)によって表される化合物、上述の医薬として許容される塩、又は上述のそのプロドラッグが脂肪酸合成を阻害し、その結果、上述の対象の上述の代謝性疾患を治療する、
を含んで成る代謝性疾患の治療方法。 - 前記の脂肪酸合成の阻害が、グルコース経路又は脂肪酸生合成経路の中の少なくとも1種類の酵素を阻害するステップを含んで成る、請求項40に記載の方法。
- 前記の脂肪酸合成の阻害が、脂肪酸シンターゼの中の少なくとも1種類の酵素を阻害するステップを含んで成って、ここで、上述の酵素が、アシルキャリアタンパク質、アセチル・トランスフェラーゼ、マロニル・トランスフェラーゼ、3-ケト-アシル-ACPシンターゼ、3-ケトアシル-ACPレダクターゼ、3-ヒドロキシ-アシル-ACPデヒドラターゼ、及びエノイル-ACPレダクターゼから成る群から選択される、請求項40に記載の方法。
- 前記の治療が、経口投与、経粘膜投与、口腔内投与、鼻腔内投与、吸入法、非経口投与、静脈内、皮下、筋肉内、舌下、及び経皮投与、並びに直腸投与から成る群から選択される、請求項40に記載の方法。
- 前記の代謝性疾患が、糖尿病又は肥満である、請求項46に記載の方法。
- 対象の癌の治療方法であって、以下のステップ:(i)上述の対象からのサンプル中の脂肪酸レベルを確認し;そして(ii)PARP阻害剤又はその代謝産物の有効量を、上述の脂肪酸レベルに基づいて投与して、脂肪酸合成を阻害し、その結果、上述の対象の上述の癌を治療する、を含んで成る前記治療方法。
- 前記の脂肪酸が、中鎖脂肪酸又は長鎖脂肪酸である、請求項46に記載の方法。
- 前記の脂肪酸合成の阻害が、グルコース経路の中の少なくとも1種類の酵素を阻害するステップを含んで成る、請求項46に記載の方法。
- 前記の脂肪酸合成の阻害が、脂肪酸生合成経路の中の少なくとも1種類の酵素を阻害するステップを含んで成る、請求項46に記載の方法。
- 前記の脂肪酸合成の阻害が、アセチルCo-A、マロニルCo-A、アセチルCo-Aカルボキシラーゼ、及び脂肪酸シンターゼから成る群から選択される少なくとも1種類の酵素を阻害するステップを含んで成る、請求項46に記載の方法。
- 前記の脂肪酸合成の阻害が、脂肪酸シンターゼの中の少なくとも1種類の酵素を阻害するステップを含んで成る、請求項46に記載の方法。
- 前記の脂肪酸シンターゼが、アシルキャリアタンパク質、アセチル・トランスフェラーゼ、マロニル・トランスフェラーゼ、3-ケト-アシル-ACPシンターゼ、3-ケトアシル-ACPレダクターゼ、3-ヒドロキシ-アシル-ACPデヒドラターゼ、及びエノイル-ACPレダクターゼを含んで成る、請求項51に記載の方法。
- 前記の脂肪酸合成の阻害が、グルコースからのアセチル-CoAの合成を阻害するステップを含んで成る、請求項52に記載の方法。
- 前記の脂肪酸合成の阻害が、アセチル-CoAからの前記の脂肪酸合成を阻害するステップを含んで成る、請求項46に記載の方法。
- 前記の長鎖脂肪酸がC:14〜C:30である、請求項47に記載の方法。
- 前記の長鎖脂肪酸が、C:14、C:16、C:18、C:18-1、C:20、C:22、又はC:24である、請求項55に記載の方法。
- 前記の阻害が、グルコース経路又は脂肪酸生合成経路の代謝産物又は分子フラックスについて分析することによって測定される、請求項46に記載の方法。
- 前記の代謝産物が、グルコース、グリコーゲン、乳酸、CO2、脂肪酸、アセチルCo-A、RNAリボース、及びDNAデオキシリボースから成る群から選択される、請求項57に記載の方法。
- 前記の代謝産物が、前記の分析のために化学的に誘導体化される、請求項58に記載の方法。
- 前記の分析が、質量分析法を含んで成る、請求項59に記載の方法。
- 前記の質量分析法が、マス・アイソトポマー分布解析である、請求項60に記載の方法。
- 前記の脂肪酸レベルを上方制御する、請求項46に記載の方法。
- 前記のPARP阻害剤又はその代謝産物が、以下の式(II):
- 前記の癌が、結腸腺癌、食道腺癌、肝臓肝細胞癌腫、扁平上皮細胞癌、膵臓腺癌、膵島細胞腫瘍、直腸腺癌、消化管間質腫瘍、胃腺癌、副腎皮質細胞癌、濾胞癌腫、乳頭癌腫、乳癌、腺管癌、小葉癌、管内癌、粘液性癌腫、葉状腫瘍、卵巣腺癌、子宮内膜腺癌、顆粒膜細胞腫瘍、粘液性嚢胞腺癌、子宮頚部腺癌、外陰部扁平上皮細胞癌、基底細胞腺癌、前立腺腺癌、骨巨細胞腫、骨肉腫、喉頭癌、肺腺癌、腎癌、膀胱癌、ウィルムス腫瘍、及びリンパ腫から成る群から選択される、請求項46に記載の方法。
- 前記の治療が、経口投与、経粘膜投与、口腔内投与、鼻腔内投与、吸入法、非経口投与、静脈内、皮下、筋肉内、舌下、及び経皮投与、並びに直腸投与から成る群から選択される、請求項46に記載の方法。
- 以下のステップ:(i)PARP阻害剤又はその代謝産物の有効量を患者に投与して、脂肪酸合成を阻害し;(ii)上述の患者からの最初と2番目のサンプル中の最初と2番目の脂肪酸レベルを比較するが、ここで、上述の最初のレベル及び上述の最初のサンプルを、上述のPARP阻害剤又はその代謝産物の投与前に入手し、そして、上述の2番目のレベル及び上述の2番目のサンプルを、上述のPARP阻害剤又はその代謝産物の投与後に入手し;そして(iii)上述の比較に基づいて、上述の患者の疾患の治療における上述のPARP阻害剤又はその代謝産物の治療有効性を決定する、を含んで成る、疾患の治療におけるPARP阻害剤又はその代謝産物の治療有効性をモニターする方法。
- 前記の脂肪酸合成の阻害が、グルコース経路又は脂肪酸生合成経路の中の少なくとも1種類の酵素を阻害するステップを含んで成る、請求項68に記載の方法。
- 前記の2番目のサンプル中の前記の2番目の脂肪酸レベルが、前記の最初のサンプル中の前記の最初の脂肪酸レベルに比べて低ければ、前記のPARP阻害剤又はその代謝産物が治療的に有効である、請求項69に記載の方法。
- 前記の2番目のサンプル中の前記の2番目の脂肪酸レベルが、前記の最初のサンプル中の前記の最初の脂肪酸レベルと比べて高ければ、前記のPARP阻害剤又はその代謝産物が治療的に無効である、請求項69に記載の方法。
- 前記の最初の脂肪酸レベルと前記の2番目の脂肪酸レベルが、アッセイ技術によって測定される、請求項69に記載の方法。
- 前記の最初の脂肪酸レベルと前記の2番目の脂肪酸レベルが、質量分析法によって測定される、請求項69に記載の方法。
- 前記の質量分析法が、マス・アイソトポマー分布解析である、請求項73に記載の方法。
- 前記のPARP阻害剤又はその代謝産物が、以下の式(II):
- 前記の疾患が、癌、心臓血管、糖尿病、又は肥満である、請求項69に記載の方法。
- 前記の投与が、経口投与、経粘膜投与、口腔内投与、鼻腔内投与、吸入法、非経口投与、静脈、筋肉内、舌下、皮下、及び経皮投与、並びに直腸投与から成る群から選択される、請求項69に記載の方法。
- 前記の最初のサンプル中の前記の最初の脂肪酸レベルが、前記の患者の病歴から決定される、請求項69に記載の方法。
- 対象のHer-2関連癌の治療方法であって、以下のステップ:(i)対象からのサンプル中のHer-2発現レベルを定量し;そして(ii)PARP阻害剤又はその代謝産物の有効量を、上述のHer-2発現レベルに基づいて投与して、上述の対象の脂肪酸合成を阻害し、その結果、上述の対象の上述のHer-2関連癌を治療する、を含んで成る前記治療方法。
- 前記の脂肪酸合成の阻害が、グルコース経路又は脂肪酸生合成経路の中の少なくとも1種類の酵素を阻害するステップを含んで成る、請求項81に記載の方法。
- 前記の脂肪酸合成の阻害が、脂肪酸シンターゼの中の少なくとも1種類の酵素を阻害するステップを含んで成って、ここで、上述の酵素が、アシルキャリアタンパク質、アセチル・トランスフェラーゼ、マロニル・トランスフェラーゼ、3-ケト-アシル-ACPシンターゼ、3-ケトアシル-ACPレダクターゼ、3-ヒドロキシ-アシル-ACPデヒドラターゼ、及びエノイル-ACPレダクターゼから成る群から選択される、請求項81に記載の方法。
- 前記のHer-2発現レベルを上方制御する、請求項81に記載の方法。
- 前記のPARP阻害剤又はその代謝産物が、以下の式(II):
- 前記の治療が、経口投与、経粘膜投与、口腔内投与、鼻腔内投与、吸入法、非経口投与、静脈内、皮下、筋肉内、舌下、及び経皮投与、並びに直腸投与から成る群から選択される、請求項86に記載の方法。
- 前記のサンプルが、癌細胞を含んで成る、請求項86に記載の方法。
- Her-2抗体を投与するステップをさらに含んで成る、請求項85に記載の方法。
- 外科手術、放射線照射療法、化学療法、遺伝子治療、免疫療法、又はその組み合わせをさらに含んで成る、請求項85に記載の方法。
- 対象の癌の治療方法であって、以下のステップ:(i)対象からのサンプル中の脂肪酸レベルを定量し;(ii)上述の対象に、以下の式:
- 前記の脂肪酸合成の阻害が、グルコース経路又は脂肪酸生合成経路の中の少なくとも1種類の酵素を阻害するステップを含んで成る、請求項91に記載の方法。
- 前記の脂肪酸合成の阻害が、脂肪酸シンターゼの中の少なくとも1種類の酵素を阻害するステップを含んで成って、ここで、上述の酵素が、アシルキャリアタンパク質、アセチル・トランスフェラーゼ、マロニル・トランスフェラーゼ、3-ケト-アシル-ACPシンターゼ、3-ケトアシル-ACPレダクターゼ、3-ヒドロキシ-アシル-ACPデヒドラターゼ、及びエノイル-ACPレダクターゼから成る群から選択される、請求項91に記載の方法。
- 前記の治療が、経口投与、経粘膜投与、口腔内投与、鼻腔内投与、吸入法、非経口投与、静脈内、皮下、筋肉内、舌下、及び経皮投与、並びに直腸投与から成る群から選択される、請求項91に記載の方法。
- 前記の癌が、Her-2関連癌、結腸腺癌、食道腺癌、肝臓肝細胞癌腫、扁平上皮細胞癌、膵臓腺癌、膵島細胞腫瘍、直腸腺癌、消化管間質腫瘍、胃腺癌、副腎皮質細胞癌、濾胞癌腫、乳頭癌腫、乳癌、腺管癌、小葉癌、管内癌、粘液性癌腫、葉状腫瘍、卵巣腺癌、子宮内膜腺癌、顆粒膜細胞腫瘍、粘液性嚢胞腺癌、子宮頚部腺癌、外陰部扁平上皮細胞癌、基底細胞腺癌、前立腺腺癌、骨巨細胞腫、骨肉腫、喉頭癌、肺腺癌、腎癌、膀胱癌、ウィルムス腫瘍、及びリンパ腫から成る群から選択される、請求項91に記載の方法。
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JP2016074741A (ja) * | 2011-03-08 | 2016-05-12 | 3−ブイ・バイオサイエンシーズ・インコーポレイテッド3−V Biosciences,Inc. | 脂質合成の複素環式モジュレーター |
US11622968B2 (en) | 2011-03-08 | 2023-04-11 | Sagimet Biosciences Inc. | Heterocyclic modulators of lipid synthesis |
JP2020514747A (ja) * | 2017-03-16 | 2020-05-21 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | Kras陽性癌の診断法及び治療法 |
Also Published As
Publication number | Publication date |
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CN101534836B (zh) | 2011-09-28 |
CA2662337A1 (en) | 2008-03-13 |
CN101534836A (zh) | 2009-09-16 |
US20120004260A1 (en) | 2012-01-05 |
AU2007292306A1 (en) | 2008-03-13 |
EP2061479A2 (en) | 2009-05-27 |
IL197350A0 (en) | 2009-12-24 |
WO2008030891A3 (en) | 2008-08-21 |
EP2061479A4 (en) | 2010-08-04 |
US20080103208A1 (en) | 2008-05-01 |
WO2008030891A2 (en) | 2008-03-13 |
US7994222B2 (en) | 2011-08-09 |
CN102379884A (zh) | 2012-03-21 |
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