AT7519

別名: AT7519M

目錄號：S1524 Purity: 99.9%

AT7519 是多種CDK抑制劑，作用于CDK1， 2， 4， 6和9時，IC50為10-210 nM，對CDK3作用效果稍弱，對CDK7幾乎沒有抑制活性。AT7519 也可抑制GSK3β的磷酸化。AT7519 可誘導凋亡。Phase 2。

AT7519 Chemical Structure

CAS: 844442-38-2

規(guī)格	價格	庫存
10mM (1mL in DMSO)	1405.32	現(xiàn)貨
5mg	903.68	現(xiàn)貨
25mg	3016.98	現(xiàn)貨
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產(chǎn)品質(zhì)控

批次： S152402 DMSO]25 mg/mL]false]Water]Insoluble]false]Ethanol]Insoluble]false 純度： 99.9%

99.9

AT7519相關產(chǎn)品

相關靶點	CDK1 CDK2 CDK3 CDK4 CDK5 CDK6 CDK7 CDK9 CLK Cdc CDK8 CDK12 CDK13 CDK19 CDK11 CDK/cyclin complexes	點擊展開
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相關化合物庫	激酶抑制劑庫 PI3K/Akt 抑制劑庫 MAPK抑制劑庫 DNA損傷/ DNA修復化合物庫細胞周期化合物庫	點擊展開

細胞實驗數(shù)據(jù)示例

細胞系	實驗類型	孵育時間	活性描述	文獻信息
A2780	Antiproliferative assay	72 hrs	Antiproliferative activity against human A2780 cells assessed as cell viability after 72 hrs by alamar blue assay, IC50=0.35μM	18656911
HCT116	Antiproliferative assay	72 hrs	Antiproliferative activity against human HCT116 cells assessed as cell viability after 72 hrs by alamar blue assay, IC50=0.082μM	18656911
MRC5	Antiproliferative assay	72 hrs	Antiproliferative activity against human MRC5 cells assessed as cell viability after 72 hrs by alamar blue assay, IC50=0.98μM	18656911
HCT116	Cytotoxicity assay	72 hrs	Cytotoxicity against human HCT116 cells assessed as growth inhibition after 72 hrs by Alamar blue assay, IC50=0.08μM	26115571
MIAPaCa2	Antiproliferative assay	72 hrs	Antiproliferative activity against human MIAPaCa2 cells after 72 hrs by prestoblue assay, IC50=0.411μM	30343954
AsPC1	Antiproliferative assay	72 hrs	Antiproliferative activity against human AsPC1 cells after 72 hrs by prestoblue assay, IC50=0.533μM	30343954
SUIT2	Antiproliferative assay	72 hrs	Antiproliferative activity against human SUIT2 cells after 72 hrs by prestoblue assay, IC50=0.557μM	30343954
BxPC3	Antiproliferative assay	72 hrs	Antiproliferative activity against human BxPC3 cells after 72 hrs by prestoblue assay, IC50=0.64μM	30343954
S2-013	Antiproliferative assay	72 hrs	Antiproliferative activity against human S2-013 cells after 72 hrs by prestoblue assay, IC50=2.77μM	30343954
Sf21	Function assay	2 hrs	Inhibition of recombinant full-length human C-terminal His6-tagged CDK1/human full-length N-terminal GST-tagged Cyclin B expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate measured after 2 hrs in presence of gamma[32P] ATP b, IC50=0.21μM	30543440
HCT116	Antiproliferative assay	72 hrs	Antiproliferative activity against human HCT116 cells assessed as reduction in cell viability after 72 hrs by cell titer glo-based luminescence assay, IC50=0.132μM	31175010
HCT116	Function assay		Inhibition of CDK1 in human HCT116 cells assessed as PP1-alpha(Thr320) phosphorylation	18656911
HCT116	Function assay		Inhibition of CDK2 in human HCT116 cells assessed as Rb(Thr321) phosphorylation	18656911
HCT116	Function assay		Inhibition of CDK2 in human HCT116 cells assessed as NPM(Thr199) phosphorylation	18656911
Sf21	Function assay		Inhibition of recombinant human full length N-terminal His6-tagged CDK5/N-terminal GST-tagged p25 expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate, Ki=0.018μM	27171036
Sf21	Function assay		Inhibition of human full length C-terminal His6-tagged CDK2/N-terminal GST-tagged cyclin A expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate, Ki=0.044μM	27171036
sf cells	Function assay		Inhibition of recombinant human N-terminal GST-tagged CDK4/cyclin D1 expressed in baculovirus infected sf cells, Ki=0.067μM	27171036
Sf21	Function assay		Inhibition of recombinant human full length C-terminal His6-tagged CDK9/cyclin T1 expressed in baculovirus infected Sf21 insect cells using PDKtide as substrate, Ki<0.1μM	27171036
Sf21	Function assay		Inhibition of human full length C-terminal His6-tagged CDK1/N-terminal GST-tagged cyclin B expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate, Ki=0.19μM	27171036
Sf21	Function assay		Inhibition of recombinant human full length C-terminal His6-tagged CDK2/N-terminal GST-tagged cyclin E expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate, Ki=0.51μM	27171036
Sf21	Function assay		Inhibition of recombinant human full length C-terminal His6-tagged CDK7/cyclin H/N-terminal GST-tagged MAT1 expressed in baculovirus infected Sf21 insect cells using cdk7 substrate peptide, Ki=2.8μM	27171036
TC32	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells	29435139
DAOY	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells	29435139
SJ-GBM2	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells	29435139
A673	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells	29435139
SK-N-MC	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells	29435139
BT-37	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells	29435139
NB-EBc1	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells	29435139
Saos-2	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells	29435139
SK-N-SH	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells	29435139
BT-12	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells	29435139
OHS-50	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells	29435139
RD	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells	29435139
MG 63 (6-TG R)	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells	29435139
Rh41	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells	29435139
A673	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for A673 cells)	29435139
SK-N-MC	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-MC cells	29435139
BT-12	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-12 cells	29435139
DAOY	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for DAOY cells	29435139
SJ-GBM2	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SJ-GBM2 cells	29435139
BT-37	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-37 cells	29435139
TC32	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for TC32 cells	29435139
U-2 OS	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for U-2 OS cells	29435139
Rh41	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh41 cells	29435139
RD	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for RD cells	29435139
Rh30	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh30 cells	29435139
Saos-2	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Saos-2 cells	29435139
OHS-50	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for OHS-50 cells	29435139
SK-N-SH	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-SH cells	29435139
HEI-OC1	Function assay		Protection against cisplatin-induced cell death in neonatal mouse HEI-OC1 cells assessed as reduction in caspase-3/7 activity, EC50=0.38μM	30091915
Sf21	Function assay		Inhibition of recombinant human full-length C-terminal His6-tagged CDK9/human full-length untagged cyclin T1 expressed in baculovirus infected Sf21 insect cells using PDKtide as substrate, IC50<0.01μM	30543440
Sf21	Function assay		Inhibition of recombinant human full-length C-terminal His6-tagged CDK3/full-length human N-terminal GST-tagged Cyclin E expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate, IC50=0.36μM	30543440
Sf21	Function assay		Inhibition of recombinant human C-terminal His6-tagged full length CDK7/untagged recombinant full length human Cyclin H/N-terminal GST-tagged recombinant full length human MAT1 expressed in baculovirus infected Sf21 insect cells using cdk7 peptide as subs, IC50=2.4μM	30543440
點擊查看更多細胞系數(shù)據(jù)

生物活性

產(chǎn)品描述

靶點

CDK9/CyclinT ^[1] (Cell-free assay)	CDK5/p35 ^[1] (Cell-free assay)	CDK2/CyclinA ^[1] (Cell-free assay)	GSK-3β ^[1] (Cell-free assay)	CDK4/CyclinD1 ^[1] (Cell-free assay)	點擊更多
<10 nM	13 nM	47 nM	89 nM	100 nM	點擊更多

體外研究(In Vitro)
體外研究活性	AT7519是ATP競爭性CDK 抑制劑，作用于CDK1 時K_i值為38 nM。 AT7519作用于所有非CDK激酶（除了GSK3β，IC50=89 nM）沒有抑制活性。AT7519作用于多種人類腫瘤細胞系，顯示有效的抗增殖活性，IC50值從作用于MCF-7的40 nM到作用于 SW620 的940 nM ，與抑制CDK1和 CDK2一致。^[1] AT7519作用于多發(fā)性骨髓瘤(MM)細胞系48小時，誘導劑量依賴性毒性IC50值從 0.5到2 μM，最敏感細胞系為MM.1S (0.5 μM)和U266 (0.5 μM) ，最抵抗細胞為MM.1R (>2 μM), 但是作用于外周血單個核細胞(PBMNC)不會誘導毒性。AT7519部分克服由 IL6 和IGF-1引起的增殖優(yōu)勢，且保護骨髓基質(zhì)細胞 (BMSCs)。AT7519 誘導RNA pol II CTD 在serine 2 和serine 5 位點快速去磷酸化, 且作用于MM 細胞通過產(chǎn)生毒性而抑制部分轉(zhuǎn)錄。AT7519通過下調(diào)GSK-3β磷酸化而誘導 GSK-3β激活，也因為 AT7519誘導凋亡，但是不抑制轉(zhuǎn)錄。^[2]
激酶實驗	體外激酶實驗
激酶實驗	輻射濾波器結合格板上進行CDK1,CDK2和GSK3-β激酶實驗。在DELFIA格式板上測定CDK5，在ELISA格式板上測定CDKs 4和 6。為了測定CDKs 1和2,相關的CDK 和0.12 μg/mL組蛋白H1在20 mM MOPS, pH 7.2, 25 mM β-甘油磷酸鹽, 5 mM EDTA, 15 mM MgCl₂, 1 mM原釩酸鈉, 1 mM DTT, 0.1 mg/mL BSA, 45 μM ATP (0.78 Ci/mmol)和不同濃度AT7519的混合物中分別溫育2或4小時。測定 GSK3-β,相關的酶和 5 μM糖原合酶肽2在10 mM MOPS pH 7.0, 0.1 mg/mL BSA, 0.001% Brij-35, 0.5% 甘油, 0.2 mM EDTA, 10 mM MgCl₂, 0.01% β-巰基乙醇, 15 μM ATP (2.31 Ci/mmol) 和不同濃度AT7519 的混合物溫育3小時。加入過量正磷酸終止反應，使用Millipore MAPH濾板過濾。然后沖洗板，加入閃爍劑，在 Packard TopCount上通過測定閃爍數(shù)而測量放射性。為了測定CDK5, CDK5/p35 和 1μM 生物素化的組蛋白H1肽段(生物素-PKTPKKAKKL) 在25 mM Tris-HCl, pH 7.5, 2.5 mM MgCl₂, 0.025% Brij-35, 0.1 mg/mL BSA, 1 mM DTT, 15 μM ATP 和不同濃度AT7519的混合物溫育30分鐘。使用EDTA終止反應,轉(zhuǎn)移到 Neutravidin包被的板上，通過兔磷酸-cdk1 底物單抗和DELFIA Eu-標記的二抗抗兔 IgG，使用時間分辨熒光測定λex=335nm,λem=620nm處熒光值，而量化磷酸化底物。為了測定CDK 4和6,用 GST- pRb769-921包被板，然后用Superblock阻斷。CDK4或6在15 mM MgCl₂, 50 mM HEPES, pH 7.4, 1 mM DTT, 1 mM EGTA, pH 8.0, 0.02% Triton X-100, 2.5% DMSO 和不同濃度AT7519混合物中溫育，加入 ATP開始反應。30分鐘后，加入 0.5 M EDTA pH 8.0終止反應。沖洗板，和一抗溫育1小時，然后在 Superblock上稀釋，隨后用堿性磷酸酶鏈接抗兔二抗再處理1小時。使用Attophos系統(tǒng)進行板顯影，然后在Spectramax Gemini計數(shù)板上讀取熒光值。使用GraphPad Prism 軟件從復制曲線中計算IC50 值。
細胞實驗	細胞系	MM.1S, MM.1R, RPMI8226, U266, RPMI8266, RPMI-Dox40, OPM1 細胞,原代 MM細胞和 PBMNCs
	濃度	溶于DMSO，濃度為 10 mM, 終濃度為 0.25-4 μM
	孵育時間	24或48小時
	方法	37^oC下不同濃度AT7519處理細胞24或48小時。通過測量MTT染料吸光度而測定細胞活性。通過測定攝入的³H胸腺嘧啶(³H-TdR)而測定DNA合成。使用Annexin V/PI染色測評凋亡。細胞是凋亡百分數(shù)是早期凋亡數(shù)(Annexin V-陽性細胞 )和晚期凋亡數(shù) (Annexin V-陽性和PI-陽性細胞)總和。
實驗圖片	檢測方法	檢測指標	實驗圖片	PMID
	Growth inhibition assay	Cell viability		20101221
	Western blot	CDK1 / CDK2 / CDK4 / Cyclin B1 / Cyclin E / CDK9 / CDK5 / CDK6 / Cyclin D1 / Cyclin A		20101221

體內(nèi)研究(In Vivo)
體內(nèi)研究活性	AT7519 按9.1 mg/kg劑量作用于 HCT116 和HT29 結腸癌移植瘤模型，每天兩次，引起早期和晚期腫瘤衰退。^[1] AT7519按 15 mg/kg 劑量作用于攜帶人類MM移植瘤的小鼠模型，抑制腫瘤生長，這和提高的caspase 3激活相關。^[2]
動物實驗	Animal Models	皮下注射MM.1S細胞的雄性SCID小鼠
	Dosages	15 mg/kg/day
	Administration	腹腔注射

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試驗信息 (data from https://clinicaltrials.gov, updated on 2024-05-22)
NCT01183949	Completed	Multiple Myeloma	Astex Pharmaceuticals Inc.\|Multiple Myeloma Research Consortium	November 2010	Phase 1\|Phase 2

參考文獻
[1] Squires MS, et al. Mol Cancer Ther, 2009, 8(2), 324-332. [2] Santo L, et al. Oncogene, 2010, 29(16), 2325-2336.

參考文獻

[1] Squires MS, et al. Mol Cancer Ther, 2009, 8(2), 324-332.
[2] Santo L, et al. Oncogene, 2010, 29(16), 2325-2336.

化學信息&溶解度

分子量	382.24	分子式	C₁₆H₁₇Cl₂N₅O₂
CAS號	844442-38-2	SDF	Download AT7519 SDF
Smiles	C1CNCCC1NC(=O)C2=C(C=NN2)NC(=O)C3=C(C=CC=C3Cl)Cl
儲存條件(自收到貨起)	3年-20°C粉狀	儲備液保存和期限建議分裝儲備液，避免反復凍融！	1年-80°C溶于溶劑
儲存條件(自收到貨起)	3年-20°C粉狀	儲備液保存和期限建議分裝儲備液，避免反復凍融！	1個月-20°C溶于溶劑

體外溶解度
批次：

DMSO : 25 mg/mL ( (65.4 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO)

Water : Insoluble

Ethanol : Insoluble

摩爾濃度計算器

體內(nèi)溶解度
批次：

現(xiàn)配現(xiàn)用，請按從左到右的順序依次添加，澄清后再加入下一溶劑

動物體內(nèi)配方計算器

實驗計算

摩爾濃度計算器

質(zhì)量	濃度	體積	分子量
=	×	×

稀釋計算器分子量計算器

動物體內(nèi)配方計算器（澄清溶液）

第一步：請輸入基本實驗信息（考慮到實驗過程中的損耗，建議多配一只動物的藥量）

給藥劑量 mg/kg 動物平均體重 g 每只動物給藥體積 μL 動物數(shù)量只

第二步：請輸入動物體內(nèi)配方組成（配方適用于不溶于水的藥物；不同批次藥物配方比例不同，請聯(lián)系Selleck為您提供正確的澄清溶液配方）

% DMSO + % + % Tween 80 + % ddH2O

%DMSO+ %

計算結果：

工作液濃度： mg/ml；

DMSO母液配制方法： mg 藥物溶于μL DMSO溶液（母液濃度mg/mL，注：如該濃度超過該批次藥物DMSO溶解度，請先聯(lián)系Selleck）；

體內(nèi)配方配制方法：取μL DMSO母液，加入μL PEG300，混勻澄清后加入μL Tween 80，混勻澄清后加入μL ddH₂O，混勻澄清。

體內(nèi)配方配制方法：取μL DMSO母液，加入μL Corn oil，混勻澄清。

注意：1. 首先保證母液是澄清的；
2.一定要按照順序依次將溶劑加入，進行下一步操作之前必須保證上一步操作得到的是澄清的溶液，可采用渦旋、超聲或水浴加熱等物理方法助溶。

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* 必填項

C1=C0/X	C1:	LOG(C1):
C2=C1/X	C2:	LOG(C2):
C3=C2/X	C3:	LOG(C3):
C4=C3/X	C4:	LOG(C4):
C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):

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