JP6742092B2 - 細胞死誘導剤、細胞増殖抑制剤及び細胞の増殖異常に起因する疾患の治療用医薬組成物 - Google Patents
細胞死誘導剤、細胞増殖抑制剤及び細胞の増殖異常に起因する疾患の治療用医薬組成物 Download PDFInfo
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- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
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Description
(2)GST−πを抑制する薬物と、GST−πとともに抑制されると合成致死性を示す恒常性維持関連タンパク質を抑制する薬物とを有効成分として含む、がん細胞の細胞増殖抑制剤。
(3)GST−πの抑制とともに合成致死性を示す上記恒常性維持関連タンパク質は、細胞周期調節タンパク質、抗アポトーシス関連タンパク質及びPI3Kシグナル伝達経路関連タンパク質からなる群から選ばれるタンパク質であることを特徴とする(1)又は(2)記載の剤。
(4)GST−πの抑制とともに合成致死性を示す上記細胞周期調節タンパク質は、ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1及びMYLKからなる群から選ばれる少なくとも1つの細胞周期調節タンパク質であることを特徴とする(3)記載の剤。
(5)GST−πの抑制とともに合成致死性を示す上記細胞周期調節タンパク質は、p21、RNPC1、CCNL1、MCM8、CCNB3及びMCMDC1からなる群から選ばれる少なくとも1つのタンパク質であることを特徴とする(3)記載の剤。
(6)GST−πの抑制とともに合成致死性を示す上記抗アポトーシス関連タンパク質は、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2及びMYO18Aからなる群から選ばれる少なくとも1つの抗アポトーシス関連タンパク質であることを特徴とする(3)記載の剤。
(7)GST−πの抑制とともに合成致死性を示す上記PI3Kシグナル伝達経路関連タンパク質は、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及びSRFからなる群から選ばれる少なくとも1つのPI3Kシグナル伝達経路関連タンパク質であることを特徴とする(3)記載の剤。
(8)上記薬物が、RNAi分子、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチド及びこれらのうち少なくとも1種を発現するベクターからなる群から選択される物質であることを特徴とする(1)又は(2)記載の剤。
(9)上記恒常性維持関連タンパク質を抑制する薬物が、当該恒常性維持関連タンパク質に作用する化合物であることを特徴とする(1)又は(2)記載の剤。
(10)アポトーシスを誘導することを特徴とする(1)記載の剤。
(11)上記がん細胞は、GST−πを高発現するがん細胞であることを特徴とする(1)又は(2)記載の剤。
(13)上記疾患ががんであることを特徴とする(12)記載の医薬組成物。
(14)上記がんはGST−πを高発現するがんであることを特徴とする(13)記載の医薬組成物。
(16)GST−πの抑制とともに合成致死性を示す上記恒常性維持関連タンパク質は、細胞周期調節タンパク質、抗アポトーシス関連タンパク質及びPI3Kシグナル伝達経路関連タンパク質からなる群から選ばれるタンパク質であることを特徴とする(15)記載のスクリーニング方法。
(17)GST−πの抑制とともに合成致死性を示す上記細胞周期調節タンパク質は、ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1及びMYLKからなる群から選ばれる少なくとも1つのタンパク質であることを特徴とする(16)記載のスクリーニング方法。
(18)GST−πの抑制とともに合成致死性を示す上記細胞周期調節タンパク質は、p21、RNPC1、CCNL1、MCM8、CCNB3及びMCMDC1からなる群から選ばれる少なくとも1つのタンパク質であることを特徴とする(16)記載のスクリーニング方法。
(19)GST−πの抑制とともに合成致死性を示す上記抗アポトーシス関連タンパク質は、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2及びMYO18Aからなる群から選ばれる少なくとも1つの抗アポトーシス関連タンパク質であることを特徴とする(16)記載のスクリーニング方法。
(20)GST−πの抑制とともに合成致死性を示す上記PI3Kシグナル伝達経路関連タンパク質は、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及びSRFからなる群から選ばれる少なくとも1つのPI3Kシグナル伝達経路関連タンパク質であることを特徴とする(16)記載のスクリーニング方法。
(21)がん細胞に対して被検物質を接触させる工程と、上記細胞における上記恒常性維持関連タンパク質の発現量を測定する工程と、被検物質の非存在下において測定した場合と比較して、当該発現量が低下した場合に上記恒常性維持関連タンパク質を抑制する薬物として選択する工程とを含む(15)乃至(20)いずれかに記載のスクリーニング方法。
(23)GST−πの抑制とともに合成致死性を示す上記恒常性維持関連タンパク質は、細胞周期調節タンパク質、抗アポトーシス関連タンパク質及びPI3Kシグナル伝達経路関連タンパク質からなる群から選ばれるタンパク質であることを特徴とする(22)記載のスクリーニング方法。
(24)GST−πの抑制とともに合成致死性を示す上記細胞周期調節タンパク質は、ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1及びMYLKからなる群から選ばれる少なくとも1つのタンパク質であることを特徴とする(23)記載のスクリーニング方法。
(25)GST−πの抑制とともに合成致死性を示す上記細胞周期調節タンパク質は、p21、RNPC1、CCNL1、MCM8、CCNB3及びMCMDC1からなる群から選ばれる少なくとも1つのタンパク質であることを特徴とする(23)記載のスクリーニング方法。
(26)GST−πの抑制とともに合成致死性を示す上記抗アポトーシス関連タンパク質は、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2及びMYO18Aからなる群から選ばれる少なくとも1つの抗アポトーシス関連タンパク質であることを特徴とする(23)記載のスクリーニング方法。
(27)GST−πの抑制とともに合成致死性を示す上記PI3Kシグナル伝達経路関連タンパク質は、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及びSRFからなる群から選ばれる少なくとも1つのPI3Kシグナル伝達経路関連タンパク質であることを特徴とする(23)記載のスクリーニング方法。
(28)がん細胞に対して被検物質を接触させる工程と、上記細胞におけるGST−πの発現量を測定する工程と、被検物質の非存在下において測定した場合と比較して、当該発現量が低下した場合にGST−πを抑制する薬物として選択する工程とを含む(22)乃至(27)いずれかに記載のスクリーニング方法。
(30)GST−πの抑制とともに合成致死性を示す上記恒常性維持関連タンパク質は、細胞周期調節タンパク質、抗アポトーシス関連タンパク質及びPI3Kシグナル伝達経路関連タンパク質からなる群から選ばれるタンパク質であることを特徴とする(29)記載のスクリーニング方法。
(31)GST−πの抑制とともに合成致死性を示す上記細胞周期調節タンパク質は、ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1及びMYLKからなる群から選ばれる少なくとも1つのタンパク質であることを特徴とする(30)記載のスクリーニング方法。
(32)GST−πの抑制とともに合成致死性を示す上記細胞周期調節タンパク質は、p21、RNPC1、CCNL1、MCM8、CCNB3及びMCMDC1からなる群から選ばれる少なくとも1つのタンパク質であることを特徴とする(30)記載のスクリーニング方法。
(33)GST−πの抑制とともに合成致死性を示す上記抗アポトーシス関連タンパク質は、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2及びMYO18Aからなる群から選ばれる少なくとも1つの抗アポトーシス関連タンパク質であることを特徴とする(30)記載のスクリーニング方法。
(34)GST−πの抑制とともに合成致死性を示す上記PI3Kシグナル伝達経路関連タンパク質は、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及びSRFからなる群から選ばれる少なくとも1つのPI3Kシグナル伝達経路関連タンパク質であることを特徴とする(30)記載のスクリーニング方法。
(35)がん細胞に対して被検物質を接触させる工程と、上記細胞におけるGST−πの発現量及びGST−πとともに抑制されると合成致死性を示す恒常性維持関連タンパク質の発現量を測定する工程と、被検物質の非存在下において測定した場合と比較して、GST−πの発現量及びGST−πとともに抑制されると合成致死性を示す恒常性維持関連タンパク質の発現量がともに低下した場合にGST−π及びGST−πとともに抑制されると合成致死性を示す恒常性維持関連タンパク質を抑制する薬物として選択する工程とを含む(29)乃至(34)いずれかに記載のスクリーニング方法。
NA(short hairpin RNA)、ddRNA(DNA-directed RNA)、piRNA(Piwi-interacting RNA)、rasiRNA(repeat associated siRNA)などの二重鎖RNA及びこれらの改変体などを含む。これらのRNAi分子は市販されているか、公知の配列情報、すなわち、配列番号1乃至30、39乃至108に示した塩基配列及び/又はアミノ酸配列に基づいて設計、作製することが可能である。
ン、塩酸ミトキサントロン、マイトマイシンC等の抗腫瘍性抗生物質、エトポシド、塩酸イリノテカン、酒石酸ビノレルビン、ドセタキセル水和物、パクリタキセル、硫酸ビンクリスチン、硫酸ビンデシン、硫酸ビンブラスチン等のアルカロイド、アナストロゾール、クエン酸タモキシフェン、クエン酸トレミフェン、ビカルタミド、フルタミド、リン酸エストラムスチン等のホルモン療法剤、カルボプラチン、シスプラチン(CDDP)、ネダプラチン等の白金錯体、サリドマイド、ネオバスタット、ベバシズマブ等の血管新生阻害剤、L−アスパラギナーゼなどを挙げることができる。
がん細胞の例として、1×105個のM7609細胞(KRAS変異ヒト大腸がん細胞)及びPANC-1細胞(KRAS変異ヒト膵臓がん細胞)を6cmシャーレに播種し、10%ウシ胎児血清(Fetal bovine serum、FBS)と0.5%L-グルタミンを添加したRoswell Park Memorial Institute 1640(RPMI 1640、Sigma社)で18時間培養した。培養条件は、特に別記しない限り37℃、5%CO2で行った。また、がん細胞の例として、0.5×105個のA549細胞(KRAS変異ヒト肺がん細胞)を6cmシャーレに播種し、10%FBSと1%L-グルタミンを添加したDulbecco’s modified Eagle’s medium(DMEM、Sigma社)で18時間培養した。さらに、がん細胞の例として、1×105個のMIA PaCa-2細胞(KRAS変異ヒト膵臓がん細胞)を6cmシャーレに播種し、10%FBSと1%L-グルタミンを添加したDMEMで18時間培養した。さらにまた、がん細胞の例として0.5×105個のHCT116細胞(KRAS変異ヒト大腸がん細胞)を6cmシャーレに播種し、10%FBSと0.5%L-グルタミンを添加したMcCoy’s 5A Medium(McCoy、Sigma社)で18時間培養した。
センス鎖:GGGAGGCAAGACCUUCAUUtt(配列番号31)
アンチセンス鎖:AAUGAAGGUCUUGCCUCCCtg(配列番号32)
P21 siRNA:
センス鎖: UCCUAAGAGUGCUGGGCAUtt(配列番号33)
アンチセンス鎖:AUGCCCAGCACUCUUAGGAtt(配列番号34)
Control siRNA:
センス鎖: ACGUGACACGUUCGGAGAAtt(配列番号35)
アンチセンス鎖:UUCUCCGAACGUGUCACGUtt(配列番号36)
GST-π siRNA-2:
センス鎖:UCUCCCUCAUCUACACCAAtt(配列番号37)
アンチセンス鎖:UUGGUGUAGAUGAGGGAGAtg(配列番号38)
実験1ではGST-π siRNA及びP21 siRNAを用いてがん細胞に対する合成致死性について実証した。本実験2では、GST-πとともに抑制されることで合成致死性を示す細胞周期調節タンパク質をスクリーニングした。
実験2では、GST-πとともに抑制されることで合成致死性を示す細胞周期調節タンパク質をスクリーニングした。本実験3では、GST-πとともに抑制されることで合成致死性を示す抗アポトーシス機能を持つタンパク質をスクリーニングした。
実験2では、GST-πとともに抑制されることで合成致死性を示す細胞周期調節タンパク質を、実験3では、GST-πとともに抑制されることで合成致死性を示す抗アポトーシス機能を持つタンパク質をスクリーニングした。本実験4では、GST-πとともに抑制されることで合成致死性を示すPI3Kシグナル伝達経路に関係するタンパク質をスクリーニングした。
本実験5では、細胞周期調節タンパク質であるMYLK(HEPATOLOGY, Vol. 44, No. 1, 2006, 152-163)について、GST-πとともに抑制されたときのA549細胞(KRAS変異ヒト肺がん細胞)に対する合成致死性を検討した。
GST-π siRNA-3:
センス鎖:CCUUUUGAGACCCUGCUGUtt(配列番号109)
アンチセンス鎖:ACAGCAGGGUCUCAAAAGGtt(配列番号110)
MYLKa:
センス鎖: CUGGGGAAGAAGGUGAGUAtt(配列番号111)
アンチセンス鎖:UACUCACCUUCUUCCCCAGtt(配列番号112)
MYLKb:
センス鎖: CAAGAUAGCCAGAGUUUAAtt(配列番号113)
アンチセンス鎖:UUAAACUCUGGCUAUCUUGtt(配列番号114)
Claims (15)
- GST−πを抑制する薬物と、GST−πとともに抑制されると合成致死性を示す恒常性維持関連タンパク質を抑制する薬物とを有効成分として含む、がん細胞の細胞死誘導剤であって、
GST−πの抑制とともに合成致死性を示す上記恒常性維持関連タンパク質は、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1、MYLK、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及びSRFからなる群から選択される少なくとも1つのタンパク質であり、
GST−πを抑制する上記薬物が、GST−πをコードするDNAに対するRNAi分子、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチド及びこれらのうち少なくとも1種を発現するベクターからなる群から選択される物質である、
上記細胞死誘導剤。 - GST−πを抑制する薬物と、GST−πとともに抑制されると合成致死性を示す恒常性維持関連タンパク質を抑制する薬物とを有効成分として含む、がん細胞の細胞増殖抑制剤であって、
GST−πの抑制とともに合成致死性を示す上記恒常性維持関連タンパク質は、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1、MYLK、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及びSRFからなる群から選択される少なくとも1つのタンパク質であり、
GST−πを抑制する上記薬物が、GST−πをコードするDNAに対するRNAi分子、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチド及びこれらのうち少なくとも1種を発現するベクターからなる群から選択される物質である、
上記細胞増殖抑制剤。 - GST−πとともに抑制されると合成致死性を示す恒常性維持関連タンパク質を抑制する上記薬物が、上記恒常性維持関連タンパク質をコードするDNAに対するRNAi分子、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチド、これらのうち少なくとも1種を発現するベクター、上記恒常性維持関連タンパク質の抗体及び上記恒常性維持関連タンパク質のドミナントネガティブ変異体からなる群から選択される物質であることを特徴とする請求項1又は2記載の剤。
- GST−πとともに抑制されると合成致死性を示す恒常性維持関連タンパク質を抑制する上記薬物が、NSC95397又はSC alpha alpha delta09であるCDC25Aの活性を抑制する薬物;butyrolactone I、quetiapine、Sorafenib及びUC2288からなる群から選択されるp21の活性を抑制する薬物;HA−100 Dihydrochloride、Staurosporine、Calphostin C、Piceatannol、A−3 Hydrochloride、H−7 Dihydrochloride、H−9 Hydrochloride、W−5、W−7、W−13 Isomer Hydrochloride、ML−7 Dihydrochloride、ML−9、Myricetin、E6 Berbamine、K−252a、K−252b及びAltenusinからなる群から選択されるMYLKの活性を抑制する薬物;SynriboであるMCL1の活性を抑制する薬物;Rapamycin、Everolimus、BEZ235、AZD8055、PI−103、Niclosamide、PP242、Timosaponin AIII、KU 0063794、AZD2014、Temsirolimus、Palomid 529、Fisetin、SF1126、CH5132799、WYE−354、Compound 401、Ridaforolimus、GSK 1059615、PF−04691502、PP121、OSI−027、WYE−125132、Umirolimus、WAY−600、WYE−687、PKI−179、PF−05212384、CAY10626、NVP−BGT226、XL−147 derivative 1、XL 388及びTorin 1からなる群から選択されるMTORの活性を抑制する薬物;Interleukin−1 Receptor−Associated−Kinase−1/4 InhibitorであるIrak1の活性を抑制する薬物;MyD88 Inhibitory Peptide Pepinh−MYD又はTJ−M2010であるMYD88の活性を抑制する薬物;BAY 11−7085、Helenalin、Caffeic Acid Phenethyl Ester、NFκB Activation Inhibitor II, JSH−23、QNZ、Andrographolide、Curcumin、Sulfasalazine、Rocaglamide、SM 7368、Sulindac Sulfide、Trichodion、CHS−828、Z−VRPR−FMK、Sodium Salicylate、4−Aminosalicylic Acid、Ethyl 3,4−Dihydroxycinnamate、CAY10512、、N−Stearoyl Phytosphingosine、Palmitic Acid Methyl Ester、9−Methylstreptimidone、Rocaglaol及びBAY 11−7082からなる群から選択されるNFKB1の活性を抑制する薬物;CUDC−907、PKI−402、PF−04691502、NVP−BGT226、IPI−145、SAR245409、ZSTK474、VS−5584、AS−605240、PIK−90、PF−4989216、TG100−115、BKM120、BEZ235 Tosylate、LY294002、PI−103、XL147、AS−252424、AS−252424、CAY10505、CH5132799、BAY 80−6946、GDC−0032、GSK1059615、CAL−130及びXL765からなる群から選択されるPIK3CGの活性を抑制する薬物;NSC23766又はW56であるRAC1の活性を抑制する薬物;4EGI−1であるEIF4Eの活性を抑制する薬物;Cpd 22又はQLT0267であるILKの活性を抑制する薬物;HS−173、CUDC−907、PKI−402、PF−04691502、NVP−BGT226、BYL719、SAR245409、ZSTK474、VS−5584、PIK-75、PIK−90、CNX1351、PF−4989216、BKM120、BEZ235 Tosylate、LY294002、PI−103、XL147、CH5132799、BAY 80−6946、GDC−0032及びXL765からなる群から選択されるPIK3CAの活性を抑制する薬物;又は、CCG−1423又はCCG−100602であるSRFの活性を抑制する薬物であることを特徴とする請求項1又は2記載の剤。
- 上記恒常性維持関連タンパク質を抑制する薬物が、当該恒常性維持関連タンパク質に作用する化合物であることを特徴とする請求項1又は2記載の剤。
- アポトーシスを誘導することを特徴とする請求項1記載の剤。
- 上記がん細胞は、GST−πを高発現するがん細胞であることを特徴とする請求項1又は2記載の剤。
- 請求項1〜7のいずれか一項記載の剤を含む、細胞の増殖異常に起因する疾患の治療用医薬組成物。
- 上記疾患ががんであることを特徴とする請求項8記載の医薬組成物。
- 上記がんはGST−πを高発現するがんであることを特徴とする請求項9記載の医薬組成物。
- GST−πとともに抑制されると合成致死性を示す恒常性維持関連タンパク質を抑制する薬物を選択することを含む、GST−πを抑制する薬物とともに使用される、がん細胞の細胞死誘導剤及び/又は細胞増殖抑制剤のスクリーニング方法であって、
GST−πの抑制とともに合成致死性を示す上記恒常性維持関連タンパク質は、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1、MYLK、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及びSRFからなる群から選択される少なくとも1つのタンパク質である、
上記スクリーニング方法。 - がん細胞に対して被検物質を接触させる工程と、上記細胞における上記恒常性維持関連タンパク質の発現量を測定する工程と、被検物質の非存在下において測定した場合と比較して、当該発現量が低下した場合に上記恒常性維持関連タンパク質を抑制する薬物として選択する工程とを含む請求項11記載のスクリーニング方法。
- GST−πを抑制する薬物を含む、がん細胞の細胞死誘導剤であって、
GST−πとともに抑制されると合成致死性を示す恒常性維持関連タンパク質を抑制する薬物と組み合わせて使用され、
GST−πの抑制とともに合成致死性を示す上記恒常性維持関連タンパク質は、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1、MYLK、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及びSRFからなる群から選択される少なくとも1つのタンパク質であり、
GST−πを抑制する上記薬物が、GST−πをコードするDNAに対するRNAi分子、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチド及びこれらのうち少なくとも1種を発現するベクターからなる群から選択される物質である、
上記細胞死誘導剤。 - GST−πを抑制する薬物を含む、がん細胞の細胞増殖抑制剤であって、
GST−πとともに抑制されると合成致死性を示す恒常性維持関連タンパク質を抑制する薬物と組み合わせて使用され、
GST−πの抑制とともに合成致死性を示す上記恒常性維持関連タンパク質は、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1、MYLK、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及びSRFからなる群から選択される少なくとも1つのタンパク質であり、
GST−πを抑制する薬物が、GST−πをコードするDNAに対するRNAi分子、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチド及びこれらのうち少なくとも1種を発現するベクターからなる群から選択される物質である、
上記細胞増殖抑制剤。 - 請求項13又14に記載の剤を含む、細胞の増殖異常に起因する疾患の治療用医薬組成物。
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US5968737A (en) * | 1996-11-12 | 1999-10-19 | The University Of Mississippi | Method of identifying inhibitors of glutathione S-transferase (GST) gene expression |
CA2571955A1 (en) * | 2004-07-09 | 2006-02-16 | The Regents Of The University Of California | Methods for treating cancer using agents that inhibit wnt16 signaling |
KR101786905B1 (ko) * | 2011-06-21 | 2017-10-19 | 닛토덴코 가부시키가이샤 | 아포토시스 유도제 |
JP6340162B2 (ja) * | 2012-12-20 | 2018-06-06 | 日東電工株式会社 | アポトーシス誘導剤 |
US10093931B2 (en) * | 2014-06-17 | 2018-10-09 | Nitto Denko Corporation | Apoptosis inducer |
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CN108064172B (zh) | 2021-08-17 |
KR20170096056A (ko) | 2017-08-23 |
RU2017126612A (ru) | 2019-01-28 |
EP3238745A1 (en) | 2017-11-01 |
RU2707746C2 (ru) | 2019-11-29 |
CN108064172A (zh) | 2018-05-22 |
US20160187319A1 (en) | 2016-06-30 |
CA2972209A1 (en) | 2016-06-30 |
AU2015368496B2 (en) | 2021-07-01 |
JP2017014185A (ja) | 2017-01-19 |
RU2017126612A3 (ja) | 2019-07-17 |
AU2015368496A1 (en) | 2017-07-27 |
EP3238745A4 (en) | 2019-02-13 |
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