JP2022522573A - L718及び/又はl792変異型治療抵抗性egfr阻害剤 - Google Patents
L718及び/又はl792変異型治療抵抗性egfr阻害剤 Download PDFInfo
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Abstract
Description
(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド(以下、「化合物A」とも称する)又はその塩を含有する、エクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有するEGFRを発現している悪性腫瘍患者を治療するための抗腫瘍剤。[Xは任意のアミノ酸残基を示す。]
更に、エクソン19欠失変異、L858R、L861Q、G719X、E709X及びエクソン20挿入変異からなる群から選択される少なくとも1つの変異を有する項1に記載の抗腫瘍剤。
更に、T790M変異を有する項2に記載の抗腫瘍剤。
L718X変異が、L718Q変異である、項1~3のいずれか一項に記載の抗腫瘍剤。
L792X変異が、L792H、L792F、又はL792Yである、項1~4のいずれか一項に記載の抗腫瘍剤。
エクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有するEGFRを発現している悪性腫瘍患者に(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を投与する工程を含む、悪性腫瘍患者の治療方法。
エクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有するEGFRを発現している悪性腫瘍患者を治療するための、(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩。
(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩の、エクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有するEGFRを発現している悪性腫瘍患者を治療するための使用。
(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩の、エクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有するEGFRを発現している悪性腫瘍患者を治療するための医薬を製造するための使用。
(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩及び薬学的に許容できる担体を含む、エクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有するEGFRを発現している悪性腫瘍患者を治療するための、医薬組成物。
[Xは任意のアミノ酸残基を示す。]
下記工程(1)~(2)を含む、悪性腫瘍患者における(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を有効成分とする抗腫瘍剤を用いた化学療法の治療効果を予測する方法:
(1)当該患者から採取された生体試料に含まれるEGFR遺伝子の変異の有無を検出する工程、及び
(2)上記工程(1)における検出の結果、EGFR遺伝子がエクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有している場合、当該患者に対する当該化学療法が十分な治療効果を示す可能性が高いと予測する工程。
[Xは任意のアミノ酸残基を示す。]
下記工程(1)~(3)を含む、悪性腫瘍患者の治療方法:
(1)当該患者から採取された生体試料に含まれるEGFR遺伝子の変異の有無を検出する工程、及び
(2)上記工程(1)における検出の結果、EGFR遺伝子がエクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有している場合、当該患者に対する(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を有効成分とする抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測する工程、及び
(3)上記工程(2)において(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を有効成分とする抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測された悪性腫瘍患者に、(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を投与する工程。
[Xは任意のアミノ酸残基を示す。]
本発明化合物Aは、例えば、WO2015/025936A1号公報に記載された製造法又は実施例に示す方法等により製造することができる。ただし、本発明化合物の製造法はこれら反応例に限定されるものではない。
本発明の対象となる腫瘍は特に制限はされないが、例えば、頭頚部癌、消化器癌(食道癌、胃癌、十二指腸癌、肝臓癌、胆道癌(胆嚢・胆管癌等)、膵臓癌、結腸直腸癌(結腸癌、直腸癌等)等)、肺癌(非小細胞肺癌、小細胞肺癌、中皮腫等)、乳癌、生殖器癌(卵巣癌、子宮癌(子宮頚癌、子宮体癌等)等)、泌尿器癌(腎癌、膀胱癌、前立腺癌、精巣腫瘍等)、造血器腫瘍(白血病、悪性リンパ腫、多発性骨髄腫等)、骨・軟部腫瘍、皮膚癌、脳腫瘍等が挙げられる。好ましくは、肺癌、乳癌、頭頸部癌、脳腫瘍、子宮癌、消化器癌、造血器腫瘍、又は皮膚癌であり、特に好ましくは肺癌である。
(1)当該患者から採取された生体試料に含まれるEGFR遺伝子の変異の有無を検出する工程、及び
(2)上記工程(1)における検出の結果、EGFR遺伝子がエクソン18及び/又はエクソン20治療抵抗性変異を有している場合、当該患者に対する当該化学療法が十分な治療効果を示す可能性が高いと予測する工程。
(1)当該患者から採取された生体試料に含まれるEGFR遺伝子の変異の有無を検出する工程、及び
(2)上記工程(1)における検出の結果、EGFR遺伝子がエクソン18及び/又はエクソン20治療抵抗性変異を有している場合、当該患者に対する(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を有効成分とする抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測する工程、及び
(3)上記工程(2)において(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を有効成分とする抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測された悪性腫瘍患者に、(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を投与する工程。
HEK293細胞を用いた変異型EGFR強制発現系における細胞内リン酸化評価結果
(阻害活性)
化合物の細胞内標的阻害活性は、Jump-In(商標) Grip(商標) HEK293細胞(Thermo Fisher Scientific Inc.)(以下、「HEK293細胞」とも称す)を用いた変異型EGFR強制発現系における細胞内EGFRリン酸化を指標に評価した。HEK293細胞は、10% 透析 ウシ胎児血清(dialyzed FBS)を含むD-MEM with GlutaMAX(商標)-I(High glucose)(Thermo Fisher Scientific Inc.)にて維持した。HEK293細胞を96ウェル平底マイクロプレートの各ウェルに1ウェルあたりの細胞数が10,000個になるように播種し、5%炭酸ガス含有の培養器中37℃で1晩培養した後、ヒトEGFR遺伝子(Del E746-A750(Ex19delとも称す)、Ex19del+T790M(+は両方の変異を有することを示す)、Ex19del+T790M+L718Q、Ex19del+T790M+L792H、Ex19del+T790M+L792F、Ex19del+T790M+L792Y、L858R、L858R+T790M、L858R+T790M+L718Q、L858R+T790M+L792H、L858R+T790M+L792F、L858R+T790M+L792Y)をコードしたpcDNATM6.2/V5―DESTベクターをOpti-MEM(商標) I(Thermo Fisher Scientific Inc.)と共にViaFect(商標) Transfection Reagent(プロメガ株式会社)を用いて導入し、再び5%炭酸ガス含有の培養器中37℃で1晩培養した。翌日、化合物A、エルロチニブ、アファチニブ及びオシメルチニブ(エルロチニブ、アファチニブ及びオシメルチニブを各々、以下、「比較化合物」とも称する)をDMSOに溶解し、DMSOもしくは培地を用いて希釈し、これを細胞の培養プレートの各ウェルに加え、5%炭酸ガス含有の培養器中37℃で6時間培養した。培養後、20% 中性緩衝ホルマリン液(和光純薬工業株式会社)を用いて細胞を固定し、ODYSSEY(商標) Blocking Buffer(PBS)(M&S TechnoSystems Inc.)により細胞をブロッキングした後、ODYSSEY(商標) Blocking Buffer(PBS)を用いて200分の1に希釈した一次抗体(EGFR Antibody Cocktail#AHR5062(Thermo Fisher Scientific Inc.)及びPhospho-EGFR Receptor(Tyr1068)Antibody#2234L(CST))に反応させ4℃で一晩静置した。翌日、ODYSSEY(商標) Blocking Buffer(PBS)を用いて800分の1に希釈した二次抗体(IRDye 800CW Goat aRabbit#926-32211及びIRDye 680RD Goat aMouse#926-68070(M&S TechnoSystems Inc.))に反応させ室温で1時間静置した。蛍光強度(Fluorescence intensity:以下「FI」とも称す)の検出は、Odyssay(商標) CLx Infrared Imaging System(LI-COR Bioscience) を用いて、蛍光波長800nm及び700nmで測定した。
T:被検化合物を添加したウェルのFI(p-EGFR/EGFR)
C:被検化合物を添加しなかったウェルのFI(p-EGFR/EGFR)。
Claims (12)
- (S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド(以下、「化合物A」とも称する)又はその塩を含有する、エクソン18のL718X変異及びエクソン2のL792X変異からなる群から選択される少なくとも1つの変異を有するEGFRを発現している悪性腫瘍患者を治療するための抗腫瘍剤。
[Xは任意のアミノ酸残基を示す。] - 更に、エクソン19欠失変異、L858R、L861Q、G719X、E709X及びエクソン20挿入変異からなる群から選択される少なくとも1つの変異を有する請求項1に記載の抗腫瘍剤。
- 更に、T790M変異を有する請求項2に記載の抗腫瘍剤。
- L718X変異が、L718Q変異である、請求項1~3のいずれか一項に記載の抗腫瘍剤。
- L792X変異が、L792H、L792F、又はL792Yである、請求項1~4のいずれか一項に記載の抗腫瘍剤。
- エクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有するEGFRを発現している悪性腫瘍患者に(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を投与する工程を含む、悪性腫瘍患者の治療方法。
- エクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有するEGFRを発現している悪性腫瘍患者を治療するための、(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩。
- (S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩の、エクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有するEGFRを発現している悪性腫瘍患者を治療するための使用。
- (S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩の、エクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有するEGFRを発現している悪性腫瘍患者を治療するための医薬を製造するための使用。
- (S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩及び薬学的に許容できる担体を含む、エクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有するEGFRを発現してい悪性腫瘍患者を治療するための、医薬組成物。
[Xは任意のアミノ酸残基を示す。] - 下記工程(1)~(2)を含む、悪性腫瘍患者における(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を有効成分とする抗腫瘍剤を用いた化学療法の治療効果を予測する方法:
(1)当該患者から採取された生体試料に含まれるEGFR遺伝子の変異の有無を検出する工程、及び
(2)上記工程(1)における検出の結果、EGFR遺伝子がエクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有している場合、当該患者に対する当該化学療法が十分な治療効果を示す可能性が高いと予測する工程。
[Xは任意のアミノ酸残基を示す。] - 下記工程(1)~(3)を含む、悪性腫瘍患者の治療方法:
(1)当該患者から採取された生体試料に含まれるEGFR遺伝子の変異の有無を検出する工程、及び
(2)上記工程(1)における検出の結果、EGFR遺伝子がエクソン18のL718X変異及びエクソン20のL792X変異からなる群から選択される少なくとも1つの変異を有している場合、当該患者に対する(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を有効成分とする抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測する工程、及び
(3)上記工程(2)において(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を有効成分とする抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測された悪性腫瘍患者に、(S)-N-(4-アミノ-6-メチル-5-(キノリン-3-イル)-8,9-ジヒドロピリミド[5,4-b]インドリジン-8-イル)アクリルアミド又はその塩を投与する工程。
[Xは任意のアミノ酸残基を示す。]
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WO2015025936A1 (ja) * | 2013-08-22 | 2015-02-26 | 大鵬薬品工業株式会社 | 新規キノリン置換化合物 |
JP2017518282A (ja) * | 2014-05-13 | 2017-07-06 | アリアド ファーマシューティカルズ, インコーポレイテッド | キナーゼ阻害のためのヘテロアリール化合物 |
WO2018079310A1 (ja) * | 2016-10-31 | 2018-05-03 | 大鵬薬品工業株式会社 | エクソン20挿入変異型egfr選択的阻害剤 |
WO2019045036A1 (ja) * | 2017-09-01 | 2019-03-07 | 大鵬薬品工業株式会社 | エクソン18及び/又はエクソン21変異型egfr選択的阻害剤 |
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WO2018079310A1 (ja) * | 2016-10-31 | 2018-05-03 | 大鵬薬品工業株式会社 | エクソン20挿入変異型egfr選択的阻害剤 |
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EP3902548A1 (en) | 2021-11-03 |
WO2020138400A1 (en) | 2020-07-02 |
AU2019417691A1 (en) | 2021-07-22 |
BR112021012687A2 (pt) | 2021-09-28 |
CN113423403A (zh) | 2021-09-21 |
KR20210110329A (ko) | 2021-09-07 |
ZA202104679B (en) | 2023-12-20 |
SG11202106986VA (en) | 2021-07-29 |
US20220072000A1 (en) | 2022-03-10 |
MX2021007852A (es) | 2021-08-11 |
JP7303303B2 (ja) | 2023-07-04 |
CA3124750A1 (en) | 2020-07-02 |
IL284330A (en) | 2021-08-31 |
TW202038965A (zh) | 2020-11-01 |
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