JP2022511929A - がん - Google Patents
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- JP2022511929A JP2022511929A JP2021533169A JP2021533169A JP2022511929A JP 2022511929 A JP2022511929 A JP 2022511929A JP 2021533169 A JP2021533169 A JP 2021533169A JP 2021533169 A JP2021533169 A JP 2021533169A JP 2022511929 A JP2022511929 A JP 2022511929A
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- JP
- Japan
- Prior art keywords
- gold complex
- cancer
- parp inhibitor
- olaparib
- complex according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
Description
R1~R5は、各々、OR6、SR6、NR6R7又はSR8であり、R1~R5のうちの少なくとも1つはSR8である;
R6及びR7は、各々独立して、H、COR9、C1-C6アルキル、C2-C6アルケニル又はC2-C6アルキニルである;
R8はAu又はAuPR10R11R12であり、
R9~R12は、各々独立してH、C1-C6アルキル、C2-C6アルケニル又はC2-C6アルキニルである);
で表される化合物、又は製薬上許容される塩、溶媒和物、互変異性形態若しくはその多形形態でありうる。
好ましくは、R1~R5の1つはSR8である。
R1~R4は、好ましくは、各々OR6である。
R6は、それが生じる場合、独立して、H又はCOR9であることが好ましい。R9は、それが生じる場合、好ましくはC1~C3アルキル、最も好ましくはメチルである。従って、一実施形態では、R6は、それが生じる場合、COCH3である。別の実施形態では、R6は、それが生じる場合、Hである。
R5は、好ましくはSR8である。
従って、金複合体は、オーラノフィン若しくはアウロチオグルコース、又は製薬上許容されるその塩、溶媒和物、互変異性形態若しくは多形形態でありうる。
酸及び塩基のヘミ塩、例えば、ヘミ硫酸塩もまた形成されてよい。
医薬組成物は、対象におけるがんの治療的改善、予防又は治療に用いうる。
金複合体及び第2PARP阻害剤は、第一態様及び第二態様に関連して定義されうる。
方法
オラパリブ耐性細胞の調製
A2780卵巣がん細胞(野生型「WT」)を10%ウシ胎児血清(FBS)含有RPMI 1640培地で培養した。
A2780細胞株は、卵巣子宮内膜腺がん腫瘍から樹立された卵巣がん細胞株である。A2780細胞株を樹立した患者は、組織採取前に腫瘍の治療を受けず、細胞株は抗がん剤や化学物質に曝露されていなかった。これは、卵巣がんに対する様々な化学物質、送達方法及び治療の効果を観察し、その効力を試験するモデルとして一般的に用いられる。
オラパリブに抵抗性を示す細胞を得るため、細胞を20μMオラパリブ添加細胞培養培地(RPMI 1640培地及び10% FBS)で1ヶ月間培養し、オラパリブに抵抗性を示すA2780細胞(R)を作製した。1ヵ月後、細胞を、10μMオラパリブ添加細胞培養培地(10% FBS添加RPMI 1640培地)中で、使用前及び耐性を維持するために最長2ヵ月間、連続培養した。
細胞を、フラスコから細胞培養培地(10% FBSを含むRPMI 1640培地)中に回収した後、計数した。細胞を培養培地で希釈し、細胞懸濁液(1000細胞/ウェル)40μLを384ウェル細胞培養プレートの各ウェルに添加した。プレートを蓋で覆い、30分間無振とうで室温に放置した。その後、プレートを37℃及び5% CO2でインキュベーターに移し、一晩放置した。
試験化合物をDMSO中に30mMの濃度で溶解し、ストック溶液を作製した。原液45 μLを384 ppプレートに移した。TECAN(EVO200)液体ハンドラーを用いて、15μLの化合物溶液を30μLのDMSOに移して、3倍10点希釈を行った。次いで、プレートを室温で1,000 RPMで1分間回転させた。次いで、希釈した化合物40 nLを化合物ソースプレートから細胞プレートに移した。次いで、細胞プレートを蓋で覆い、37℃及び5% CO2のインキュベーターに入れ、120時間放置した。化合物による処理の72時間後に、以下に述べるように検出を行った。
CellTiter Glo(登録商標)試薬を解凍し、室温に平衡化した。次いで、細胞プレートをインキュベーターから取り出し、室温で15分間平衡化した。その後、各ウェルにCellTiter Glo(登録商標)試薬を30μL添加した(培地に対して1:1)。内容物を、軌道振盪機で2分間混合して細胞溶解を誘導した後、プレートを室温で30分間インキュベートした。次いで、ルミネセンスをEnvisionリーダー(Perkin Elmer)で測定した。
阻害活性は、以下の式:
阻害(%)=100×(Lumベヒクル-Lum試料)/(Lumベヒクル-Lumブランク)
(式中、Lumベヒクルは0.1% DMSOで処理した細胞の発光であり、Lumブランクは培地中の細胞である)を用いて算出した。
Y= 底部+(頂部-底部)/(1+10^((LogIC50-X)*ヒル傾斜))
を用いて、曲線に当てはめて算出した。
結果を表1~表4、図1、図2に示す。
方法
方法は実施例1に記載したとおりであった。各試験では、細胞をオーラノフィン又はオーラノフィン及びオラパリブの併用で処理した。オーラノフィンの濃度は一定に保ったが、オラパリブの濃度は変化させた。
すべての試験を3回実施し、阻害の平均値を算出した。
混合物中の相乗作用又は拮抗作用は、Colby法を用いて評価しうる。この方法を用いると、相乗作用や拮抗作用がなければ、AとBの混合物の期待結果(E)が計算される。Eは、次式:
E = X + Y -XY/100
を用いて計算しうる。
その結果を表5、6、図3、4に示す。
低濃度のオラパリブについては、オラパリブ単独での阻害率を求める試験を実施していないため、予想値を算出することができなかった。しかし、観察された阻害率は依然として比較的高く、60pMのオラパリブ濃度まで相乗効果が観察されたことを示す。この結論は、低濃度のニラパリブ及びタラゾパリブについて、観察された値が予想値よりも有意に高かったことにより裏付けられた。
上記の結果は、PARPiを単独使用した場合には抵抗性を示す細胞が、第2活性剤との併用では感受性を示すとは考えられないことを鑑みると、特に驚くべきことである。
方法
方法は、HCC1937細胞系を用いた以外は、実施例1及び2に記載の通りであった。
その結果を表7、8、図5、6に示す。
方法
方法は、オーラノフィンの代わりにアウロチオグルコースを用いた以外は、実施例1及び2に記載の通りであった。
オラパリブ、ニラパリブ及びタラゾパリブのオラパリブ抵抗性A2780卵巣がん細胞に対する増殖阻害能を表2(上記)に示す。一方、アウロチオグルコース(ATG)の当該細胞に対する増殖阻害能を表9及び図7に示す。
Claims (22)
- 既知のがん治療に抵抗性のがんの治療に用いられる金複合体。
- 前記金複合体は、前記式(I)で表される化合物である、請求項2に記載の金複合体。
- R1~R4は各々、OR6である、請求項3又は4に記載の金複合体。
- R6は、各々独立して、H又はCOR9であり、かつR9は各々、C1-C3アルキルである、請求項3~5のいずれか一項に記載の金複合体。
- R6は、各々COCH3である、請求項6に記載の金複合体。
- R6は、各々にHである、請求項6に記載の金複合体。
- R8は、AuPR10R11R12であり、R10~R12は各々、C2-C4アルキルである、請求項3~8のいずれか一項に記載の金複合体。
- R8はAuである、請求項3~8のいずれか一項に記載の金複合体。
- 前記金複合体は、オーラノフィン若しくはアウロチオグルコース、又はその製剤上許容される塩、溶媒和物、互変異性形態若しくは多形形態である、請求項1に記載の金複合体。
- 前記がんは、固形腫瘍又は固形がんである、請求項1~3のいずれか一項に記載の金複合体。
- 前記がんは、血液がん、大腸がん、脳がん、乳がん、子宮頸がん、子宮内膜がん、胃がん、肝がん、肺がん、卵巣がん、膵臓がん、前立腺がん又は皮膚がんである、請求項1~3のいずれか一項に記載の金複合体。
- 前記がんは、第1PARP阻害剤による治療に抵抗性であるがんである、前記いずれか一項に記載の金複合体。
- 前記がんに罹患している患者は、前記第1PARP阻害剤で既に治療されている、請求項14に記載の金複合体。
- 第1PARP阻害剤は、第1PARP1阻害剤である、請求項14又は15に記載の金複合体。
- 前記金複合体は、第2PARP阻害剤と併用される、請求項1~3のいずれか一項に記載の使用の金複合体。
- 前記第2PARP阻害剤は、第2PARP1阻害剤である、請求項17に記載の金複合体。
- 前記第2PARP1阻害剤は、アウロチオリンゴ酸、アウロチオグルコース(ATG)、ルカパリブ、オラパリブ、ニルパリブ、タラゾパリブ、ベリパリブ、パミパリブ、2X-121又はオーラノフィンである、請求項18に記載の金複合体。
- 前記第2PARP1阻害剤は、ルカパリブ、オラパリブ、ニルパリブ、タラゾパリブ、ベリパリブ又はパミパリブである、請求項19に記載の使用のための金複合体。
- (i)金複合体、(ii)第2PARP阻害剤、及び(iii)製剤上許容されるビヒクルを含む、がんを治療するための医薬組成物。
- (i)金複合体、(ii)第2PARP阻害剤、及び(iii)製剤上許容されるビヒクルの治療有効量を接触させる工程を含む、請求項21に記載の組成物を作製する方法。
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US20220000911A1 (en) | 2022-01-06 |
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GB201913957D0 (en) | 2019-11-13 |
GB2592555A (en) | 2021-09-08 |
WO2021058967A1 (en) | 2021-04-01 |
JP7422152B2 (ja) | 2024-01-25 |
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