KR20200063443A - Plk1의 활성 억제제를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물 - Google Patents
Plk1의 활성 억제제를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물 Download PDFInfo
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- KR20200063443A KR20200063443A KR1020180149112A KR20180149112A KR20200063443A KR 20200063443 A KR20200063443 A KR 20200063443A KR 1020180149112 A KR1020180149112 A KR 1020180149112A KR 20180149112 A KR20180149112 A KR 20180149112A KR 20200063443 A KR20200063443 A KR 20200063443A
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- pteridine
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Abstract
Description
도 2는, 본 발명의 일 구현예에 따른 화합물들의 FP assay 분석결과 및 IC50를 나타낸 그래프이다.
도 3은, 본 발명의 일 구현예에 따른 화합물들의 FP assay 분석결과를 나타낸 그래프, 및 IC50를 나타낸 것이다.
도 4는, 본 발명의 일 구현예에 따른 화합물들의 FP assay 분석결과를 나타낸 그래프, 및 IC50를 나타낸 것이다.
도 5a 및 도 5b는, 본 발명의 실시예 3에 따라 화합물 2(M2)의 암세포들의 성장 저해능을 측정한 그래프이다.
도 5c는 본 발명의 실시예 3에 따라 JIMT1 세포에서 M2 및 M2 변형체의 암세포 성장 저해능을 측정한 그래프이다.
도 6은, 본 발명의 실시예 3에 따라 화합물 2(M2), 화합물 3(M4), 화합물 4(M21), 및 sorafenib 의 간암세포주의 성장 저해능을 측정한 그래프이다.
도 7은, 본 발명의 실시예 3에 따라 화합물 3(M4)의 암세포들의 성장 저해능을 측정한 그래프이다.
도 8은, 본 발명의 실시예 3에 따라 화합물 3(M4)의 암세포들의 성장 저해능을 측정한 그래프이다.
도 9a는, 본 발명의 실시예 3에 따라 화합물 5(M23), 및 화합물 6(M25)의 간암세포주 성장 저해능을 측정한 그래프이다.
도 9b는 본 발명의 실시예 3에 따라 HepG2 세포에서 M2 및 M2 변형체의 암세포 성장저해능을 측정한 그래프이다.
도 9c는 본 발명의 실시예 3에 따라 SNU449 세포에서 M2 및 M2 변형체의 암세포 성장저해능을 측정한 그래프이다.
도 10은, 본 발명의 실시예 3에 따라 화합물 2(M2) 단독, 및 화합물 2(M2)와 BI2536을 혼합 처리 시 간암세포주 성장 저해능을 측정한 그래프이다.
도 11은, 본 발명의 실시예 4에 따라, 본 발명의 일 구현예에 따른 화합물들의 처리 시 중심체에 위치하는 r-tubulin과 PLK1, 염색체(DAPI)의 상호 위치관계를 확인한 것이다.
도 12는, 본 발명의 실시예 4에 따라 NCAPG2의 염색체 팔 및 동원체에서의 염색 정도를 나타낸 사진과 그래프이다.
도 13은, 본 발명의 실시예 5에 따라 화합물 2(M2)를 처리하였을 경우 세포 주기에 미치는 영향을 보여주는 그래프이다.
도 14a는, HepG2 세포에서 M2 또는 BI2536 처리 후 상대적 세포 면적을 나타낸 것이다.
도 14b는 M2 또는 BI2536 처리된 HepG2 세포에서 핵 염색을 통해 관찰한 이미지를 나타낸 것이다.
도 15a는, HepG2 세포에 M2와 BI2536을 각각 처리한 후 유세포 분석을 수행한 결과이다.
도 15b는, HepG2 세포에 M2와 BI2536을 각각 용량을 증가시키며 처리한 후 세포사멸 결과를 그래프로 나타낸 것이다.
도 16은, 본 발명의 실시예 8에 따라 화합물 4 및 DMSO를 각각 마우스 복강주사 후, 폐, 심장, 간, 신장, 비장 및 피부를 적출하여 조직병리학적으로 분석한 사진이다.
도 17은, 본 발명의 실시예 8에 따라 종양의 크기와 마우스 체중을 나타낸 그래프이다.
도 18은, 본 발명의 실시예 8에 따라 적출된 암생성 조직의 외관을 보여주는 사진이다.
도 19는, 본 발명의 실시예 8에 따라 적출된 조직에서 PLK1의 발현을 비교하기 위해 PLK1에 대한 면역조직학적 염색을 실시하였으며, PLK1 자체의 발현 차이가 현저하진 않았으나 세포분열기 중의 세포수는 감소하는 것을 보여주는 사진이다.
도 20a는, 본 발명의 실시예 9에 따라 마우스에 M2 처리 후 이식된 종양의 육안형태 및 MRI 이미지를 나타낸 것이다.
도 20b는, 상기 도 20a의 MRI 영상을 이용하여 이식된 종양의 부피 변화 및 M2의 종양성장 감소 효과를 그래프로 나타낸 것이다.
도 20c는, 본 발명의 실시예 9에 따라 이식된 종양 조직에서 세포분열기 중의 세포수가 감소하는 것을 나타낸 것이다.
도 20d는, 상기 도 20c의 조직병리학적 관찰을 이용하여 각 처리군에서 계산된 Mitotic index를 나타낸 그래프이다.
도 21a는, 본 발명의 실시예 9에 따라 마우스에 M2 처리 후 이식된 종양의 크기 변화를 MRI 이미지를 통해 나타낸 것이다.
도 21b는, 본 발명의 실시예 9에 따라 마우스에 M2 처리 후 이식된 종양의 최종 무게를 나타낸 것이다.
도 21c는, 본 발명의 실시예 9에 따라 마우스에 M2 처리 후 이식된 종양의 부피 변화를 나타낸 것이다.
도 22a는, 본 발명의 실시예 10에 따라 대조군(control)에서 마우스에 이식된 종양의 MRI 이미지를 나타낸 것이다.
도 22b는, 본 발명의 실시예 10에 따라 M2를 처리한 군에서 마우스에 이식된 종양의 MRI 이미지를 나타낸 것이다.
도 22c는, 본 발명의 실시예 10에 따라 BI2536 처리한 군에서 마우스에 이식된 종양의 MRI 이미지를 나타낸 것이다.
도 22d는, 본 발명의 실시예 10에 따라 M2 또는 BI2536를 처리한 군에서 종양의 부피 종양의 무게 및 체중의 변화를 비교한 그래프이다.
NO. | IUPAC NAME | 구조식 |
화합물 1 | 2,4-Dioxo-1,2,3,4-tetrahydrobenzo[g]pteridine-7-carboxylic acid |
|
화합물 2 (M2) | 10-methyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione | |
화합물 3 (M4) | 8-chloro-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione |
|
화합물 4 (M21) |
10-methyl-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione | |
화합물 5 (M23) |
8-amino-1,3-dimethyl-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione | |
화합물 6 (M25) |
8-amino-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione | |
화합물 7 (M202) |
7,8,10-trimethyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione | |
화합물 8 (M203) |
7,10-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridine-8-carbaldehyde | |
화합물 9 (M204) |
4,10-Dihydro-7,8,10-trimethyl-2,4-dioxobenzo[g]pteridine-3(2H)-acetic Acid |
|
화합물 10 (M206) |
3-{7,8-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridin-10-yl}propanenitrile |
|
화합물 11 (M209) |
10-[2-(3-methylphenoxy)ethyl]-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione | |
화합물 12(M217) | 7,8-Dimethyl-10-[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]benzo[g]pteridine-2,4-dione | |
화합물 13(M218) | [(2R,3S,4S)-5-(7,8-dimethyl-2,4-dioxobenzo[g]pteridin-10-yl)-2,3,4-trihydroxypentyl] dihydrogen phosphate |
Claims (10)
- 하기 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물.
[화학식 1]
[화학식 2]
상기 화학식 1 또는 2에서,
R1은 H, 알킬, 또는 -CnH2nCOOH(n은 1 내지 4의 정수)이고,
R2는 H, 알킬, -CmH2mCN, -CmH2mOR5, 또는 -CpH2p(CH(OH))qR6 이고, R5는 하나 이상의 C1-3의 알킬로 치환된 페닐이며, R6는 H, 알킬 또는 -OPH2O3 이고, m은 2 내지 4의 정수이고, p는 1 내지 3의 정수이고, q는 2 내지 4의 정수이고,
R3는 H, 할로겐, -NH2, 알킬, 또는 -CH=O 이고,
R4는 H, 알킬, -COOH, 또는 -CX3 이고, X는 할로겐임.
- 제1항에 있어서, 상기 화학식 1 또는 2로 표시되는 화합물은 하기 화합물로 이루어지는 군으로부터 선택되는 것을 특징으로 하는, 약학적 조성물 :
2,4-Dioxo-1,2,3,4-tetrahydrobenzo[g]pteridine-7-carboxylic acid ;
10-methyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione ;
8-chloro-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione ;
10-methyl-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione ;
8-amino-1,3-dimethyl-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione ;
8-amino-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione ;
7,8,10-trimethyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione ;
7,10-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridine-8-carbaldehyde ;
4,10-Dihydro-7,8,10-trimethyl-2,4-dioxobenzo[g]pteridine-3(2H)-acetic Acid ;
3-{7,8-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridin-10-yl}propanenitrile ;
10-[2-(3-methylphenoxy)ethyl]-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione ;
7,8-Dimethyl-10-[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]benzo[g]
pteridine-2,4-dione ; 및
[(2R,3S,4S)-5-(7,8-dimethyl-2,4-dioxobenzo[g]pteridin-10-yl)-2,3,4-trihydroxypentyl] dihydrogen phosphate
- 제1항에 있어서, 상기 암은 간암, 유방암, 혈액암, 자궁경부암, 및 전립선암으로 이루어진 군으로부터 선택되는 1종 이상인 것을 특징으로 하는, 약학적 조성물.
- 제1항에 있어서, 상기 화합물은 PLK1(polo-like kinase 1)의 PBD(polo-box domain)에 결합하는 것을 특징으로 하는, 약학적 조성물.
- 제1항에 있어서, 상기 약학적 조성물은 암세포의 성장을 저해하는 것을 특징으로 하는, 약학적 조성물.
- 제1항에 있어서, 상기 약학적 조성물은 암세포의 세포사멸(apoptosis)을 유도하는 것을 특징으로 하는, 약학적 조성물.
- 하기 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암 개선용 건강기능식품 조성물.
[화학식 1]
[화학식 2]
상기 화학식 1 또는 2에서,
R1은 H, 알킬, 또는 -CnH2nCOOH(n은 1 내지 4의 정수)이고,
R2는 H, 알킬, -CmH2mCN, -CmH2mOR5, 또는 -CpH2p(CH(OH))qR6 이고, R5는 하나 이상의 C1-3의 알킬로 치환된 페닐이며, R6는 H, 알킬 또는 -OPH2O3 이고, m은 2 내지 4의 정수이고, p는 1 내지 3의 정수이고, q는 2 내지 4의 정수이고,
R3는 H, 할로겐, -NH2, 알킬, 또는 -CH=O 이고,
R4는 H, 알킬, -COOH, 또는 -CX3 이고, X는 할로겐 임.
- 제8항에 있어서, 상기 화학식 1 또는 2로 표시되는 화합물은 하기 화합물로 이루어지는 군으로부터 선택되는 것을 특징으로 하는, 건강기능식품 조성물 :
2,4-Dioxo-1,2,3,4-tetrahydrobenzo[g]pteridine-7-carboxylic acid ;
10-methyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione ;
8-chloro-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione ;
10-methyl-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione ;
8-amino-1,3-dimethyl-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione ;
8-amino-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione ;
7,8,10-trimethyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione ;
7,10-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridine-8-carbaldehyde ;
4,10-Dihydro-7,8,10-trimethyl-2,4-dioxobenzo[g]pteridine-3(2H)-acetic Acid ;
3-{7,8-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridin-10-yl}propanenitrile ;
10-[2-(3-methylphenoxy)ethyl]-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione ;
7,8-Dimethyl-10-[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]benzo[g]
pteridine-2,4-dione ; 및
[(2R,3S,4S)-5-(7,8-dimethyl-2,4-dioxobenzo[g]pteridin-10-yl)-2,3,4-trihydroxypentyl] dihydrogen phosphate
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PCT/KR2018/014944 WO2020111325A1 (ko) | 2018-11-28 | 2018-11-29 | Plk1의 활성 억제제를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물 |
CN201880099899.3A CN113164483B (zh) | 2018-11-28 | 2018-11-29 | 含有plk1抑制剂作为活性成分的用于预防或治疗癌症的药物组合物 |
JP2021530151A JP7268153B2 (ja) | 2018-11-28 | 2018-11-29 | Plk1の活性抑制剤を有効成分として含む癌の予防または治療用薬学的組成物 |
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