KR20080008407A - 항신생물의 화합물 및 이를 포함하는 약학적 조성물 - Google Patents
항신생물의 화합물 및 이를 포함하는 약학적 조성물 Download PDFInfo
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- KR20080008407A KR20080008407A KR1020077028594A KR20077028594A KR20080008407A KR 20080008407 A KR20080008407 A KR 20080008407A KR 1020077028594 A KR1020077028594 A KR 1020077028594A KR 20077028594 A KR20077028594 A KR 20077028594A KR 20080008407 A KR20080008407 A KR 20080008407A
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Abstract
본 발명은 카제인 키나제 2 효소 기질 인산화반응 영역 또는 그 주위와의 화합물의 특이적 상호 작용을 통해 인산화 반응 발생을 차단하기에 적절한 잘 한정된 구조를 갖는 인실리코(in silico) 분자 모델링에 의해 유도된 화학적 화합물에 관한 것이다. 본 발명은 또한 이들 화합물을 함유하는 약학적 조성물, 및 종양형성과정과 관련된 질환 또는 증상을 치료하기 위한 제제 또는 치료제의 조제에 있어서의 이들의 용도를 포함한다.
카제인 키나제 2, 인산화 반응, 인실리코 분자 모델링
Description
본 발명은 분자약학의 분야에서 기술되어질 수 있는 것으로 특히 종양학과 관련되고, 그리고 더욱 자세하게는 인실리코(컴퓨터 모의 실험; in silico) 분자 모델링에 의해 얻어진 화학적 화합물로, 카제인 키나제 2 기질 상에 인산화반응 사이트를 이들의 직접적 또는 간접적 상호작용을 통해 차단함으로써 명확한 세포독성 작용과 항종양 효과를 갖는 화합물 및 이들의 약학적 조성물에 관한 것이다.
카제인 키나제 2 (CK2)는 세포 증식의 증가에 포함되어지는 세린/트레오닌 효소로, 이것은 악성 전이의 과정 동안에 주요한 세포간의 위치화에 핵심이 된다 (Tawfic S., Yu S., Wang H., et al. (2001) Protein kinase CK2 signal in neoplasia. Histol . Histopathol. 16:573-582). 더욱이 인간 면역결핍 바이러스(HIV) 및 간염 C 바이러스(HCV)의 질병전개에 대한 몇몇 주요 바이러스 단백질이 CK2 기질로 보고되어 있다 (Meggio F., Marin O., et al. (2001) Mol Cell Biochem 227:145-151; Franck N., Le Seyec J., et al. (2005) Hepatitis C virus NS2 protein is phosphorylated by the protein kinase CK2 and targeted for degradation to the proteasome. J Virol. 79:2700-2008).
전세계에 알려진 다른 군들의 발견은 또한 CK2의 측정된 준위가 상피 조직 유래의 다른 고형 종양에서 정상 조직에 대해 3 내지 7 배 정도 높은 범위로 존재하는 것을 또한 확인하였으며 (Tawfic S., Yu S., et al. (2001) Protein kinase CK2 signal in neoplasia. Histol Histopatol . 16:573-582; Faust R.A., Gapany M., et al (1996) Elevated protein kinase CK2 activity in chromatin of head and neck tumors: association with malignant transformation. Cancer Letters 101:31-35), 게다가 CK2 효소의 인산화 반응 활성이 종양 진행에 대한 강력한 마커를 구성하는 세포의 악성 형질전환에서 아주 중요한 것이라는 것을 확인하였으며 (Seldin D.C., Leder P. (1995) Casein Kinase IIa transgene-induced murine lymphoma: relation to theileroiosis in cattle. Science 267:894-897), 한편 CK2의 과발현은 케스케이드 Wnt/베타-카테닌에서의 상향 조절에 의해 유방 세포의 종양형성을 유도하는 것을 확인하였다 (Landesman-Bollag E., Romien-Mourez R., et al (2001) Protein Kinase CK2 in mammary gland tumorigenesis. Oncogene 20:3247-3257). 최근의 발견은 또한 CK2가 크로마틴 리모델링 (Barz T., Ackenmann K., et al. (2003) Genome-wide expression screens indicate a global role for protein kinase CK2 in chromatin remodelling. J Cell Sci. 116:1563-1577) 및 세포 생존의 제어 (Unger G.M., Davis A.T., Slaton J.W., Ahmed K. (2004) Protein kinase CK2 as regulator of cell survival: implications for cancer therapy. Curr Cancer Drug Targets, 4:77-84)와 같은 몇몇 다른 프로세스에 필수적인 역할을 한다는 것을 제한하였다. 암의 전개 과정을 이해하기 위한 가장 중요한 것 중에 는 CK2 매개 인산화 반응이 세포 생존에 대한 매우 강력한 신호이며, 따라서 이 효소는 세포 생리학에 대한 항 어팝토시스의 매개자로 고려되어진다는 것을 입증하는 발견이 있었다 (Ahmed K., Gerber D.A., Cochet C. (2002) Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell Biol, 12:226-229; Torres J., Rodriguez J., et al (2003) Phosphorylation-regulated cleavage of the tumour suppressor PTEN by caspase-3: implications for the control of protein stability and PTEN-protein interactions. J Biol Chem, 278:30652-60).
상기한 발견에 기초하여, CK2 매개 인산화 반응은 암에 대한 치료적 관여를 위한 강력한 타겟으로 사용되어지기에 적절한 생화학적 사건으로서 확인되어져, 이러한 사건의 모든 강력한 저해제를 이러한 상태의 치료를 위한 전도 유망한 후보 군으로 여기게 했다. 현재까지, 세계적으로 몇 가지의 연구 군이, a)CK2 효소의 직접적인 저해, 또는 b)모든 CK2 기질에 공통적으로 기술된 산성 영역 근처의 인산화 반응 사이트의 차단과 같은 두 가지의 실험적 접근법으로 CK2 매개 인산화 반응을 저해하기 위한 다른 전략을 개발하여 오고 있다.
양 접근법에 대해, 본 저자는 CK2 매개 인산화 반응 이벤트의 저해가, 암 치료를 위한 약물의 발견에 매우 긍정적인 타겟으로 CK2 실험적 타당성 검사를 함축하는 종양 세포에 대한 어팝토시스의 유도를 생성하는 개념을 입증할 수 있었다.
이 레터의 예는 쥬르캇 세포에 마이크로 몰 농도 범위로 강력한 어팝토시스 및 카스파제 의존성 퇴화 유도자로서 시험된 4,5,6,7-테트라브로모트리아졸 (TBB) 과 같은 효소의 직접적인 저해자이다 (Ruzzene M., Penzo D., Pinna L. (2002) Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells. Biochem J., 364:41-47). 또한, 항-센스 올리고뉴클레오티드류를 사용함으로써 CK2 효소의 발현을 저해함에 의한 마우스에서 실험적 암 모델에서 실험실적 어팝토시스의 효과 및 항종양 작용. (Guo C., Yu S., et al. (2001) A potential role of nuclear matrix-associated protein kinase CK2 in protection against drug-induced apoptosis in cancer cells. J Biol Chem, 276:5992-5999; Slaton J.W., et al. (2004) Induction of apoptosis by antisense CK2 in human prostate cancer xenograft model. Mol Cancer Res. 2:712-721).
안트라퀴논 유도체류, 후라보노이드류, 및 할로겐화 아조벤질이미다졸류와 같은 다른 화합물들이 CK2 ATP 결합 사이트 저해자로 기술되어져 있고 (Sarno S., et al. (2002) Toward the rational design of protein kinase casein kinase-2 inhibitors. Pharmacol Therapeutics 93:159-168), 그리고 5-옥소-5,6-디히드로인돌로(1,2-a)퀴나졸린-7-일 초산 (IQA)이 높은 처리량 스크리닝을 사용하여 선택적인 CK2 저해자로 보고되어 있다 (Vangrevelinghe E., et al. (2003) Biochemical and three-dimensional-structural study of the specific inhibition of protein kinase CK2 by [5-oxo-5,6-dihydroindolo-(1,2-a)quinazolin-7-yl]acetic acid (IQA). J. Med . Chem. 46:2556-2662).
상기 언급한 화합물들은 50% 저해 농도 (IC50)에 대해 마이크로 몰 범위에서 그들의 CK2 활성 저해 효과를 보여주었지만, 암의 실험적 모델에서 항종양 작용의 어떤 증거도 보고되어 있지 않다.
CK2 활성을 저해하기 위한 다른 접근법은 기질 상의 인산화 반응 사이트를 방해하는 것으로, 특허출원 WO 03/054002 및 Cancer Res . 64:7127-7129에 기재된 Perea S.E 등의 논문(2004) "Antitumor effect of a novel proapoptotic peptide impairing the phosphorylation by the protein kinase CK2."으로, 저자들은 암 예비-임상적 모델에서 종양 세포의 세포독성 및 항종양 효과를 보는, 기질 사이트 상에 CK2 매개 인산화 반응을 차단하기 위한 환형 펩티드 과의 용도를 제안하는 것으로 제한되어졌다. 그러나, 기술되어진 펩티드는 그 자체로는 세포 내로 관통할 수 없고 따라서 이것들에 용융되어 지는 멤브레인 투과 펩티드를 필요로 한다는 한계를 가진다.
일반적인 관점에서, 소형 분자에 비교할 때, 펩티드의 사용은 순환, 분해에서의 생체 내에서의 감소된 안전성의 단점을 가져, 경구 투여제로 제형화 하는데 매우 어렵고 그리고 이들은 세포 내로 용이하게 전달되어 지지 않는다 (Ludger Wess, Isogenica: Improving peptides, Biocentury October 25, 2004). 문헌들에 광범위하게 기술된 펩티드류의 다른 문제점은 보다 빠른 소거, 이들의 면역성의 잠재성, 그리고 치료적 복용량 당 이들의 비용은 비-펩티드 약물에 일반적으로 월등한 것으로 알려져 있다는 것이다.
치료적 제제 후보로서 상기 언급된 환형 펩티드의 용도에 대한 잠재적인 제한을 고려하여, 본 발명은 먼저 효소 기질 상에 인산화 반응 사이트와의 직접적 또는 간접적 상호작용에 의한 CK2 매개 인산화 반응을 저해할 수 있는 화학적 분자를 기술하고 그리고 암의 실험적 모델에서 세포독성 및 항종양 효과를 이끌어 낸다.
여기서 기술된 화학적 화합물은 이들이 다음 작용의 하나 또는 몇 가지를 성취할 수 있게 하는 아주 명확한 화학적 구조를 가진다.
A: 기질에 CK2 효소의 결합을 직접적 또는 간접적 방식으로 차단하도록, 기질 인산화 반응 사이트에 화합물의 결합을 허용하는 것.
B: CK2 효소의 결합은 여전히 허용하지만 인산수용체 세린에 인산기의 전이를 직접적 또는 간접적 방식으로 차단하도록, 기질 인산화 반응 영역에 화합물의 결합을 허용하는 것.
C: CK2 효소의 결합이나 인산수용체 세린에 인산기의 전이를 직접적으로 또는 간접적으로 차단하는 방식과 같은, 기질 인산화 반응 영역 또는 그 주위, 또는 양자에 배좌 구조 변화를 이끌어 내도록, CK2 기질 단백질에 화합물의 결합을 허용하는 것.
따라서 기술된 화합물은 CK2 매개 인산화 반응의 생화학적 이벤트에 대한 이들의 저해 능에 의해 주로 특징되어진다.
특정 실현화에서, 본 발명은 분자의 일 부분에 다음 다섯 가지의 구조적 기로 구분되고 지시된 전자적 상보결합이 연속적 방식으로 결합된 화학적 요소의 발생에 의해 제한된 특정한 화학적 구조에 의해 특징된 화학 분자에 관한 것이다:
I. N-[C(sp2)]1,2,3-N
II. N-[C(sp2)]1,2-[C(sp3)]1,2,3-N
III. N-[C(sp3)]1,2,3-N
IV. N-C(sp2)-[C(sp3)]1,2-C(sp2)-N
V. N-C(sp3)-[C(sp2)]1,2-C(sp3)-N
이러한 구조적 부류에 속하는 몇 가지 화합물들은 아래에 나타나 있다:
상술한 분자는 이 효소에 대해 잘 정의된 교감 인산화 반응 사이트의 철저한 분자 모델링에 의해 청구된 기능(Meggio F., Pinna L.A. (2003) One-thousand-and-one substrates of protein kinase CK2. The FASEB J. 17:349-368), CK2 효소에 결합하는 분자에 의한 그의 타당성 조사 및 더욱이 대략적인 수 일백이십만 화합물을 갖는 우리 실험실에서 만든 화학적 다양성 데이터 베이스로의 거대한 분자 스크리닝에 의한 분석에 대하여 잘 기술되어진다.
본 발명은 또한 기술된 화합물의 어떤 동종의 변형체를 포함한다. 동종의 변형체에 대해 정의로는 여기서 기술된 것에 유사하거나 또는 비유사한 화학적 특성의 분자이지만, 이들이 어떤 CK2 기질의 CK2 매개 인산화 반응을 저해하는 얻어진 작용으로 여기에 기술된 화합물과 동일한 효과를 나타내도록 하는 화학적 구조를 갖는다.
본 발명의 바람직한 실시형태로, 또 다른 것으로는 하나 또는 그 이상의 화학적 화합물, 및/또는 이들의 약학적으로 허용될 수 있는 이들의 염이 단독으로 또는 다른 약학적으로 허용된 담체 또는 부형제와 같이 포함되는 약학적 조성물이다. 또한, CK2 효소가 병리학적 역할을 할 수 있는 살아있는 조직의 암 및/또는 다른 상태를 치료하기 위하여, 생체 외, 생체 내 또는 신체와 연결된 장치에서 종양 세포의 증식을 저해하기 위한 약물의 제조에 기술된 화학적 화합물의 사용도 본 발명의 일 부분이다.
기술된 화학적 분자는 최소한의 아미노산 시퀀스 S/T-X-X-E/D의 인산화 반응을 저해하는 그의 능력에 의해 한정되며 X는 바람직하기로는 라이신 또는 아르기닌이 다른 아미노산이고 더욱이 이러한 시퀀스를 갖지 않고 이 종류의 아미노산에 결합하고 그리고 이들에 의해 저해된 이들의 CK2 매개 인산화 반응을 갖는 다른 단백질이다.
본 발명에서 기술된 화학적 분자의 정의에 대해서는, 본 발명자 등은 이 효소에 대해 잘 정의된 교감 인산화 반응 사이트의 철저한 분자 모델링 (Meggio F., Pinna L.A. (2003) One-thousand-and-one substrates of protein kinase CK2. The FASEB J. 17:349-368), CK2 효소에 결합하는 분자에 의한 그의 타당성 조사 및 더욱이 대략적인 수 일백이십만 화합물을 갖는 우리 실험실에서 만든 화학적 다양성 데이터 베이스로의 거대한 분자 스크리닝에 의한 분석을 수행하였다.
평균 이상의 계산된 결합에너지 값을 갖는 모든 화합물이 제일 라운드에서 양성으로 선택되었고, 보다 제한적인 선택 값으로 선별하는 제이 라운드에 제공되어 지고, 그리고 구조적인 규칙성을 추출하기 위해 분석되고, 제이 선별 라운드에서 선택된 화합물의 화학적 구조는 계산된 결합 에너지에 대한 가장 가능한 값을 수득하기 위해 최적화된다. 얻어진 화합물은 고성능 액체 크로마토그라피를 사용하여 합성되고, 정제되었으며, 적외선 분광기, 질량분석법 및 핵 자기 공명에 의해 분석되고 그리고 마지막으로 생체 내에서 및 생체 외에서 그들의 유효성이 평가되었다. 본 발명에 따르면, 기술된 화학적 화합물은 CK2 매개 인산화 반응 이벤트를 저해하는 능력에 있어서 균일하게 유효하다.
본 발명에서 기술된 화학적 화합물은 용량에 의존하는 방식으로, 어떤 세포 투과 제제와 연계할 필요 없이 인간 종양 세포에 세포독성을 이끌어 낸다. 이런 증거는 그들 자신에 대한 화학적 분자가 세포의 기관에 의해 전달되어 질 수 있고, 세포의 내면으로 그 타겟에 도달되어 질 수 있는 것을 보여주는 이전의 발명들과 합치되어 진다 (Meggio F, Pagano MA, et al. (2004) Inhibition of protein kinase CK2 by condensed polyphenolic derivatives. An in vitro and in vivo study. Biochemistry . 43:12931-12936).
동등하게, 나노몰 범위에서 화학적 화합물의 생체 외 세포 독성 연구에 대해 IC50 값을 발견하는 것은 매우 매력적인 것이다. 이들 결과는 CK2 인산화 반응 영역에 대한 저해제로서 이미 보고된 환형 펩티드에 비하여 여기에 기술된 화합물의 고양된 세포독성 활성을 나타낸다.
생체 외 결과와 합치하여, 본 발명에 대한 화학적 화합물은 국부적으로 뿐 아니라 체계적으로 투여되어질 때 강력한 항종양 효과를 가진다. 동등하게 본 발명에 대한 화학적 화합물은 0.5 내지 2 mg/Kg 만큼 낮은 복용량에서, 이미 기술된 환형 펩티드에 대한 기술된 복용량에 대해 10 내지 20 배 감소를 나타내는 항종양 효과를 나타낸다는 것이 입증되었다.
도 1은 마우스에 이식된 인간 종양 모델에서 화학적 화합물의 항종양 효과이다.
이하, 본 발명은 다음의 실시예를 통하여 상세하게 설명되어 진다.
실시예
1:
인실리코
분자
모델링에
의한 화합물의
셀렉션
.
컴퓨터의 모델을 사용함에 의해, 대규모의 가상 선별로 전개된 몇 가지의 화합물이 다음의 표에 나타난 바와 같이 리셉터-리간드 복합체의 계산된 결합 에너지에 대한 높은 값에 기초하여 선택되었다. 이 근사 에너지 값은 우리 실험실에서 개발된 컴퓨터의 프로그램을 사용하여 배좌 및 에너지 성분의 철저한 분석을 고려하여 평가되어 졌다.
화학적 화합물 | 계산된 에너지 - kJ mol -1 | 화학적 화합물 | 계산된 에너지 - kJ mol -1 |
Peptide P15 | NA | C31421 | 34.6 |
C30401 | 37.5 | C31422 | 34.6 |
C30402 | 38.2 | C314 23 | 32.8 |
C30403 | 40.1 | C31424 | 32.8 |
C30404 | 40.6 | C32425 | 41.6 |
C30405 | 39.8 | C33426 | 30 |
C30406 | 36.3 | C33427 | 39.5 |
C30407 | 32.4 | C34428 | 32.8 |
C30408 | 37.6 | C34429 | 31.4 |
C30409 | 41.2 | C34430 | 32.6 |
C30410 | 40.7 | C34431 | 31.4 |
C30411 | 38.2 | C34432 | 31.6 |
C30412 | 35.5 | C34433 | 34.4 |
C30413 | 32.6 | C34434 | 35.1 |
C30414 | 30.1 | C34435 | 34.8 |
C30415 | 34.7 | C34436 | 34.1 |
C31416 | 38 | C34437 | 33.8 |
C31417 | 32.1 | C34438 | 30.9 |
C31418 | 32.6 | C34439 | 40.6 |
C31419 | 31.4 | C34440 | 38.9 |
C31420 | 30 |
실시예
2: 전형적인
CK2
기질의 인산화 반응에 대한 기술된 화학적 화합물의 효과.
이 분석은 기질로 글루타티온 S-트랜스퍼라제(GST) 용융 단백질로서 대장균(E. coli)에서 발현된 인간 파필로마 바이러스 타입 16 (VHP-16)으로부터 종양단백질 E7을 사용하여, 생체 외 인산화 반응을 수행하는 것으로 구성된다. 얻어진 E7-GST는 그런 다음 글루타티온-세파로스(Pharmacia) 어피니티 크로마토그라피에 의해 정제된다. 효소적 반응 전에, E7-GST는 다른 농도의 화학적 화합물과 37oC에서 한 시간 동안 예비 배양된다. 반응은 50 ml Tris:HCL 25 mM pH 7.5 buffer, 1 mCi의 32P- gATP, 100 mM ATP, 수지를 포함하는 40 ml E7-GST, 0.2 M NaCl, 10 mM MgCl 및 1 유닛의CK2 효소(Promega)로 구성된 혼합물에서 수행되어, 37oC에서 40분 동안 진행되게 한다. 반응 후 수지는 0.5 ml의 반응 버퍼로 삼 회 수세되고 그리고 마지막으로 E7-GST의 인산화 반응 준위가 10% 폴리아크릴아미드 겔 전기영동(PAGE)으로 분석되었다. 인산화된 단백질의 투시법은 건조된 PAGE 젤에 엑스선 민감성 필름을 노출함에 의해 수행되었고, 그리고 정량화는 필름의 밀도계 분석에 의해 수행되었다. IC50 값은 각각 복용량-효과 곡선을 사용하여 측정되었다. IC50 값은 50%의 효소 활성에 영향을 미치는 저해 농도로 여겨진다. 병행하여 대조 실험은 비교로서 포함되어져, CK2 기질 인산화 반응 사이트에 대한 저해제로서 이미 보고된 환형 펩티드 P15를 동일한 조건에서 분석하였다.
다음 표 2 결과는 여기에 기술된 화합적 화합물이, IC50 값으로부터 간주되는 것으로서 전형적인 CK2 기질에 대한 효과적인 저해제라는 것을 나타낸다. 주목할만한 사실은, 단지 마이크로 몰 범위에서 활성으로, 이미 보고된 환형 펩티드와 비교하여 화학적 화합물의 가장 높은 저해 능을 나타낸다는 것이다.
화학적 화합물 | 저해 농도 50 (IC50) nM | 화학적 화합물 | 저해 농도 50 (IC50) nM |
Peptide P15 | 2 000±20 | C31421 | 30±8 |
C30401 | 26±11 | C31422 | 24±5 |
C30402 | 30±5 | C314 23 | 26±8 |
C30403 | 34±9 | C31424 | 32±13 |
C30404 | 20±8 | C32425 | 35±3 |
C30405 | 27±10 | C33426 | 29±8 |
C30406 | 32±7 | C33427 | 31±7 |
C30407 | 22±10 | C34428 | 25±7 |
C30408 | 29±2 | C34429 | 21±12 |
C30409 | 31±6 | C34430 | 30±4 |
C30410 | 40±9 | C34431 | 32±6 |
C30411 | 27±10 | C34432 | 29±7 |
C30412 | 30±3 | C34433 | 2610 |
C30413 | 24±9 | C34434 | 28±5 |
C30414 | 23±9 | C34435 | 34±3 |
C30415 | 33±8 | C34436 | 30±2 |
C31416 | 39±6 | C34437 | 27±4 |
C31417 | 2811 | C34438 | 31±1 |
C31418 | 32±5 | C34439 | 33±5 |
C31419 | 30±4 | C34440 | 26±4 |
C31420 | 25±7 |
실시예
3:
CK2
교감 사이트의 인산화 반응에 대한 기술된 화학적 화합물의 효과.
이 분석은 기질로 CK2기질에 대한 최적화된 교감 인산화 반응 영역으로 광범위하게 수용되는 시퀀스 RRREEETEEE를 사용하여, 생체 외 인산화 반응을 수행하는 것으로 구성된다.
효소적 반응 전에, 기질 펩티드는 다른 농도의 화학적 화합물과 37oC에서 한 시간 동안 예비 배양된다. 반응은 50 ml Tris:HCL 25 mM pH 7.5 buffer, 1 mCi의 32P- gATP, 100 mM ATP, 수지를 포함하는 40 ml E7-GST, 0.2 M NaCl, 10 mM MgCl 및 1 유닛의CK2 효소(Promega)로 구성된 혼합물에서 수행되어, 37oC에서 10분 동안 진행되게 한다. 반응 후 5 ml의 반응 혼합물이 왓트만 PE-81 페이퍼 필터에 적용되고 그리고 10 mM H3PO4로 4회 수세되고, 마지막으로 페이퍼에 합체된 방사성활성이 평가되고 그리고 각 샘플에 대한 cpm 값은 CK2 효소 활성과 직접적으로 관련된다.
IC50 값은 각각 복용량-효과 곡선을 사용하여 측정되었다. IC50 값은 50%의 효소 활성에 영향을 미치는 저해 농도로 여겨진다. 병행하여 대조 실험은 비교로서 포함되어져, CK2 기질 인산화 반응 사이트에 대한 저해제로서 이미 보고된 환형 펩티드 P15를 동일한 조건에서 분석하였다.
다음 표 3 결과는 여기에 기술된 화합적 화합물이, IC50 값으로부터 간주되는 것으로서 전형적인 CK2 기질에 대한 효과적인 저해제라는 것을 나타낸다. 주목할만한 사실은, 단지 마이크로 몰 범위에서 활성으로, 이미 보고된 환형 펩티드와 비교하여 화학적 화합물의 가장 높은 저해 능을 나타낸다는 것이다.
화학적 화합물 | 저해 농도 50 (IC50) nM | 화학적 화합물 | 저해 농도 50 ( IC50 ) nM |
Peptide P15 | 5 000±162 | C31421 | 50±8 |
C30401 | 62±11 | C31422 | 74±5 |
C30402 | 74±7 | C314 23 | 76±4 |
C30403 | 58±9 | C31424 | 62±1 |
C30404 | 61±8 | C32425 | 65±13 |
C30405 | 57±10 | C33426 | 79±9 |
C30406 | 60±7 | C33427 | 517 |
C30407 | 73±11 | C34428 | 65±10 |
C30408 | 79±5 | C34429 | 61±4 |
C30409 | 55±6 | C34430 | 70±4 |
C30410 | 54±7 | C34431 | 55±3 |
C30411 | 66±12 | C34432 | 67±7 |
C30412 | 71±5 | C34433 | 76±8 |
C30413 | 64±11 | C34434 | 78±1 |
C30414 | 68±9 | C34435 | 64±6 |
C30415 | 72±10 | C34436 | 66±2 |
C31416 | 69±6 | C34437 | 71±9 |
C31417 | 78±11 | C34438 | 81±7 |
C31418 | 72±5 | C34439 | 63±12 |
C31419 | 60±8 | C34440 | 56±4 |
C31420 | 55±11 |
실시예
4: 여기에 기술된 화합물의 인간 종양 세포에 대한 효과.
인간 비 소형 세포 폐 암종(Non Small Cells Lung Carcinoma)으로부터 H-125 세포가 96 웰 플레이트(Costar)에 Dulbecco (DMEM) 배지(Gibco)에 2x104 cell/ml 밀도로 접종되고 그리고 태아 송아지 혈청(Gibco)으로 보충된다. 24시간 후, 여기에 기술된 화학적 화합물이 배양된 배지에 0.5 내지 100 nM 사이의 범위로 부가되어지고, 혼합물은 72시간 동안 5%CO2에서 37oC에서 배양되고, 종단에는 20 ml의 1.90 mg/ml MTS 용액이 부가된다. 이 플레이트는 부가적으로 한 시간 동안 동일한 배양 조건에서 유지되고 492 nm에서 흡광도가 판독되었다. 결과는 어떠한 화합물도 부가되지 않은 대조군에 대한 성장 백분율로 평가되었고, 그리고 IC50 값은 각각 복용량-효과 곡선을 사용하여 측정되었다. IC50 값은 50%의 효소 활성에 영향을 미치는 저해 농도로 여겨진다. 병행하여 대조 실험은 비교로서 포함되어져, CK2 기질 인산화 반응 사이트에 대한 저해제로서 이미 보고된 환형 펩티드 P15를 동일한 조건에서 분석하였다.
다음 표 4 결과는 여기에 기술된 화합적 화합물이, IC50 값으로부터 간주되는 것으로서 배양된 인간 종양 세포에 대해 강력한 생체 외 세포 독성 효과를 가진다는 것을 나타낸다. 주목할만한 사실은, 단지 마이크로 몰 범위에서 활성으로, 이미 보고된 환형 펩티드와 비교하여 화학적 화합물의 가장 높은 저해 능을 나타낸다는 것이다.
화학적 화합물 | 저해 농도 50 (IC50) nM | 화학적 화합물 | 저해 농도 50 (IC50) nM |
펩티드 P15 | 70 000±562 | C31421 | 120±18 |
C30401 | 103±21 | C31422 | 114±5 |
C30402 | 98±7 | C314 23 | 106±9 |
C30403 | 128±9 | C31424 | 162±11 |
C30404 | 115±18 | C32425 | 115±12 |
C30405 | 104±12 | C33426 | 109±19 |
C30406 | 97±17 | C33427 | 151±7 |
C30407 | 103±11 | C34428 | 165±12 |
C30408 | 119±8 | C34429 | 131±4 |
C30409 | 104±6 | C34430 | 140±14 |
C30410 | 114±7 | C34431 | 155±23 |
C30411 | 126±15 | C34432 | 127±7 |
C30412 | 91±15 | C34433 | 116±18 |
C30413 | 130±11 | C34434 | 108±21 |
C30414 | 118±9 | C34435 | 124±16 |
C30415 | 112±10 | C34436 | 116±22 |
C31416 | 109±6 | C34437 | 131±9 |
C31417 | 118±21 | C34438 | 111±17 |
C31418 | 123±15 | C34439 | 123±25 |
C31419 | 132±18 | C34440 | 136±32 |
C31420 | 125±10 |
실시예
5: 누드 마우스에 이식된 인간 종양 모델에 대한 항종양 효과.
6 내지 8주령의 암컷 BalbC 누드 마우스가 이 분석에 사용되었다. 이 모델에 종양 이식을 위해, 250 ㎕ PBS에 재현탁된 5 000 000 H-125 세포가 동물의 배면 영역에 주사되어 졌다. 일단 종양이 50 mm3의 대략적 부피로 촉진될 수 있으면, 200 ㎍의 화합물 C32425, C33426 및 C33427의 직접적인 매일의 투여가 5일 동안 수행된다. 도 1에 도시된 바와 같이, 화학적 화합물의 투여는 유의성 있는 항종양 반응을 나타낸다. 이러한 결과는 CK2 매개 인산화 반응을 저해하는 화학적 화합물은 실험적 발병을 위한 관련 모델에서 항종양 반응을 이끌어 낼 수 있다는 것을 나타낸다.
Claims (4)
- 다음 필요조건의 하나 또는 몇 가지를 충족함을 특징으로 하는 카제인 키나제 2 (CK2) 매개 인산화 반응을 차단하는 화학적 화합물:a. 기질에 CK2 효소의 결합을 직접적 또는 간접적 방식으로 차단하도록, 기질 인산화 반응 사이트에 화합물의 결합.b. 인산수용체 세린에 인산기의 전이를 직접적 또는 간접적 방식으로 차단.c. 기질 인산화 반응 영역 또는 그 주위, 또는 양자에 배좌 구조 변화를 이끌어 내도록, CK2 기질 단백질에 a 또는 b에 따른 작용으로 직접적 또는 간접적 방식으로 결합.
- 제 1항에 있어서, 화학적 구조는 다음 다섯 가지의 구조적 기에 따른 적어도 하나로부터 선택되고 지시된 전자적 상보결합이 연속적 방식으로 결합된 화학적 요소에서의, 분자의 어떤 부위에 발생에 의해 한정된 화학적 화합물 및 이들의 동종성 변형체:I. N-[C(sp2)]1,2,3-NII. N-[C(sp2)]1,2-[C(sp3)]1,2,3-NIII. N-[C(sp3)]1,2,3-NIV. N-C(sp2)-[C(sp3)]1,2-C(sp2)-NV. N-C(sp3)-[C(sp2)]1,2-C(sp3)-N
- 청구항 1 및 2의 어느 하나에 정의되어 진 것과 같은 화학적 화합물 및/또는 이들의 약학적으로 허용 가능한 이들의 염의 하나 또는 그 이상을 다른 약학적으로 허용된 담체 또는 부형제와 같이 포함하는, CK2 효소가 병리적 역할을 가질 수 있거나 및/또는 다른 종양형성과정과 관련된 질환 또는 증상을 치료하기 위한 약학적 조성물.
- 살아있는 조직의 암 및/또는 CK2 효소가 병리적 역할을 가질 수 있는 다른 증상을 치료하기 위해, 생체 내에서, 생체 외에서 또는 신체 연계 장치에서 종양 세포의 증식의 저해를 위한 치료제의 제조에 청구항 1 및 2의 어느 하나에 정의되어진 화합물의 사용.
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AT509045B1 (de) * | 2010-01-29 | 2011-06-15 | Planta Naturstoffe Vertriebsges M B H | Verbindungen zur behandlung von asthma bronchiale |
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WO2018230537A1 (ja) * | 2017-06-13 | 2018-12-20 | 国立研究開発法人国立がん研究センター | 発がん抑制剤 |
CN107903196A (zh) * | 2017-11-08 | 2018-04-13 | 南京大学 | 刺激和增强保护性免疫反应化合物、制备方法及其用途 |
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US2673859A (en) * | 1950-09-15 | 1954-03-30 | Allied Chem & Dye Corp | Production of urea derivatives |
US3957791A (en) * | 1972-09-25 | 1976-05-18 | Sandoz, Inc. | Hydroxyalkyl-piperazino-quinoline nitrates |
US6962698B1 (en) * | 1998-02-17 | 2005-11-08 | Gamida Cell Ltd. | Methods of controlling proliferation and differentiation of stem and progenitor cells |
JP2003523166A (ja) * | 1998-09-29 | 2003-08-05 | ガミダ セル リミテッド | 幹細胞および前駆細胞の増殖と分化を制御する方法 |
CU23225A1 (es) * | 2001-12-20 | 2007-08-30 | Ct Ingenieria Genetica Biotech | PéPTIDOS PARA EL TRATAMIENTO DEL CáNCER ASOCIADO AL VIRUS PAPILOMA HUMANO (VPH) Y DE OTROS TUMORES EPITELIALES |
US20090270456A1 (en) * | 2004-01-09 | 2009-10-29 | Masaichi Hasegawa | Novel chemical compounds |
WO2006065724A2 (en) * | 2004-12-14 | 2006-06-22 | Regents Of The University Of Minnesota | Casein kinase 2 antisense therapy |
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DK1892245T3 (en) | 2015-11-02 |
MY140530A (en) | 2009-12-31 |
RU2007146169A (ru) | 2009-06-20 |
CA2607298A1 (en) | 2006-11-16 |
JP5117377B2 (ja) | 2013-01-16 |
US8748411B2 (en) | 2014-06-10 |
ZA200709692B (en) | 2008-11-26 |
WO2006119713A2 (es) | 2006-11-16 |
CN101203522A (zh) | 2008-06-18 |
ES2550959T3 (es) | 2015-11-13 |
WO2006119713A3 (es) | 2007-03-01 |
BRPI0608806A2 (pt) | 2011-03-15 |
RU2404987C2 (ru) | 2010-11-27 |
JP2008543735A (ja) | 2008-12-04 |
US20090215730A1 (en) | 2009-08-27 |
PT1892245E (pt) | 2015-11-12 |
AU2006246204B2 (en) | 2012-04-19 |
DK2474528T3 (da) | 2014-10-27 |
MX2007014216A (es) | 2008-02-07 |
CN101203522B (zh) | 2011-06-08 |
PT2474528E (pt) | 2014-10-28 |
EP2474528A1 (en) | 2012-07-11 |
AU2006246204A1 (en) | 2006-11-16 |
EP1892245B1 (en) | 2015-07-29 |
CA2607298C (en) | 2014-12-09 |
EP2474528B1 (en) | 2014-09-24 |
ES2516240T3 (es) | 2014-10-30 |
EP1892245A2 (en) | 2008-02-27 |
AR057012A1 (es) | 2007-11-07 |
CU23431B6 (es) | 2009-10-16 |
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