鍩烘湰淇℃伅
| 鍒嗗瓙寮廃/td> | C22H27FN4O2·C4H6O5 |
| 鍒嗗瓙閲廃/td> | 532.56 |
| 鐔旂偣 | 185-192 |
| 鎶樺厜鐜?n20D) | 1.61 |
| MDL缂栫爜 | MFCD08282795 |
浜у搧鎻忚堪
Sunitinib Malate鏄竴绉嶅闈剁偣RTK鎶戝埗鍓傦紝浣滅敤浜嶸EGFR2 (Flk-1)鍜 PDGFRβ锛屽湪鏃犵粏鑳炶瘯楠屼腑IC50鍒嗗埆涓?0 nM 鍜? nM锛屼篃浼氭姂鍒禼-Kit鐨勬椿鎬с€侟/p>
闈剁偣锛圛C50 & Targe锛堻/b>
FGFR1,2.9μM
PDGFRβ,2nM
VEGFR2,80nM
浣撳鐮旂┒
Sunitinib涔熸槸鏈夋晥鐨刢-Kit鎶戝埗鍓傦紝IC50涓?11 nM銆俒1] Sunitinib鏄湁鏁堢殑ATP绔炰簤鎬EGFR2 (Flk1)鍜孭DGFRβ鎶戝埗鍓傦紝 Ki 鍒嗗埆涓? nM鍜 8 nM,浣滅敤浜嶸EGFR2鍜 PDGFR 姣斾綔鐢ㄤ簬FGFR-1, EGFR, Cdk2, Met, IGFR-1, Abl,鍜 src閫夋嫨鎬ч珮10澶氬€嶃€係unitinib 浣滅敤浜庤娓呴ゥ楗垮鐞嗙殑琛ㄨ揪VEGFR2鎴朠DGFRβ鐨凬IH-3T3缁嗚優, 鎶戝埗VEGF渚濊禆鐨 VEGFR2纾烽吀鍖栧拰 PDGF渚濊禆鐨凱DGFRβ纾烽吀鍖栵紝IC50鍒嗗埆涓?0 nM鍜 10 nM銆係unitinib鎶戝埗VEGF璇卞鐨勮娓呴ゥ楗垮鐞嗙殑 HUVECs 澧炴畺锛孖C50涓?0 nM, 涓旀姂鍒禤DGF璇卞鐨勮繃閲忚〃杈綪DGFRβ鎴 PDGFRα鐨凬IH-3T3缁嗚優锛孖C50鍒嗗埆涓?9 nM鍜 69 nM銆俒2] Sunitinib 鎶戝埗閲庣敓鍨婩LT3, FLT3-ITD,鍜孎LT3-Asp835纾烽吀鍖栵紝IC50鍒嗗埆涓?50 nM, 50 nM, 鍜 30 nM銆係unitinib 鎶戝埗MV4;11鍜 OC1-AML5缁嗚優澧炴畺锛孖C50鍒嗗埆涓? nM 鍜? nM, 涓旇瀵煎噵浜★紝杩欑浣滅敤瀛樺湪鍓傞噺渚濊禆鎬с€ [3]
浣撳唴鐮旂┒
涓庝綋鍐呭ぇ閲忎笖閫夋嫨鎬ф姂鍒禫EGFR2鎴朠DGFR纾烽吀鍖栧拰淇″彿鐩镐竴鑷? Sunitinib姣忓ぉ鎸 20-80 mg/kg 鍓傞噺澶勭悊澶氱绉绘鐦ゆā鍨嬶紝鍖呮嫭HT-29, A431, Colo205, H-460, SF763T, C6, A375,鎴 MDA-MB-435锛屽叿鏈夊箍娉涗笖鏈夋晥鐨勬姉鐧屾椿鎬э紝杩欑浣滅敤瀛樺湪鍓傞噺渚濊禆鎬с€係unitinib 姣忓ぉ鎸 80 mg/kg鍓傞噺澶勭悊锛屾寔缁?1澶╋紝浣垮叓鍙紶涓湁鍏彧鑲跨槫瀹屽叏琛伴€€锛屼笖鍦ㄥ鐞嗙粨鏉熷悗锛岃瀵?10澶╋紝鑲跨槫涓嶄細澶嶅彂銆備娇鐢 Sunitinib杩涜绗簩杞鐞嗭紝浠嶇劧楂樻晥浣滅敤浜庣涓€杞病鏈夊畬鍏ㄨ“閫€鐨勮偪鐦ゃ€係unitinib澶勭悊SF763T鑳惰川鐦わ紝瀵艰嚧鑲跨槫MVD鏄捐憲闄嶄綆锛岄檷浣庯綖40%銆係U11248 澶勭悊锛屽畬鍏ㄦ姂鍒惰〃杈捐崸鍏夌礌閰剁殑PC-3M绉绘鐦ょ敓闀匡紝鑰岃偪鐦ゅ昂瀵告病鏈夊噺灏忋€俒2] Sunitinib 姣忓ぉ鎸?0 mg/kg鍓傞噺澶勭悊锛屾樉钁楅樆鏂毊涓婱V4;11 (FLT3-ITD)绉绘鐦ょ敓闀匡紝涓斾綔鐢ㄤ簬FLT3-ITD楠ㄩ珦绉绘鐦ゆā鍨嬶紝鎶戝埗寤堕暱鐨勫鍛姐€俒3]
婵€閰跺疄楠孅/b>
Biochemical Tyrosine Kinase Assays:
IC50 values for Sunitinib against VEGFR2 (Flk-1) and PDGFRβ are determined using glutathione S-transferasefusion proteins containing the complete cytoplasmic domain of the RTK. Biochemical tyrosine kinase assays to quantitate the trans-phosphorylation activity of VEGFR2 (Flk-1) and PDGFRβ are performed in 96-well microtiter plates precoated (20 μg/well in PBS; incubated overnight at 4 °C) with the peptide substrate poly-Glu,Tyr (4:1). Excess protein binding sites are blocked with the addition of 1-5% (w/v) BSA in PBS. Purified GST-fusion proteins are produced in baculovirus-infected insect cells. GST-VEGFR2 and GST-PDGFRβ are then added to the microtiter wells in 2 × concentration kinase dilution buffer consisting of 100 mM HEPES, 50 mM NaCl, 40 μM NaVO4, and 0.02% (w/v) BSA. The final enzyme concentration for GST-VEGFR2 or GST-PDGFRβ is 50 ng/mL. Twenty-five μL of diluted Sunitinib are subsequently added to each reaction well to produce a range of inhibitor concentrations appropriate for each enzyme. The kinase reaction is initiated by the addition of different concentrations of ATP in a solution of MnCl2 so that the final ATP concentrations spanned the Km for the enzyme, and the final concentration of MnCl2 is 10 mM. The plates are incubated for 5-15 minutes at room temperature before stopping the reaction with the addition of EDTA. The plates are then washed three times with TBST. Rabbit polyclonal antiphosphotyrosine antisera are added to the wells at a 1:10,000 dilution in TBST containing 0.5% (w/v) BSA, 0.025% (w/v) nonfat dry milk, and 100 μM NaVO4 and incubated for 1 hour at 37 °C. The plates are then washed three times with TBST, followed by the addition of goat antirabbit antisera conjugated with horseradish peroxidase (1:10,000 dilution in TBST). The plates are incubated for 1 hour at 37 °C and then washed three times with TBST. The amount of phosphotyrosine in each well is quantitated after the addition of 2,2鈥?azino-di-[3-ethylbenzthiazoline sulfonate] as substrate.
缁嗚優瀹為獙
Cell lines: RS4;11, MV4;11, 鍜 OC1-AML5
Concentrations: 婧朵簬DMSO,缁堟祿搴︿负锝?0 μM
Incubation Time: 24 鍜?8 灏忔椂
Method: 缁嗚優鍦ㄥ惈0.1% FBS 鐨勫煿鍏诲熀涓婇ゥ楗垮鐞嗚繃澶滐紝鐒跺悗鍔犲叆Sunitinib鍜 FL (50 ng/mL; FLT3-WT)銆傚煿鍏?8灏忔椂鍚庯紝浣跨敤 Alamar Blue 妫€娴嬫垨鍙伴厷钃濈粏鑳炴椿鍔涙娴嬫祴瀹氬娈栥€傚姞鍏unitinib 24灏忔椂鍚庯紝娴嬮噺鍑嬩骸锛岄€氳繃Western blotting娴嬪畾caspase-3姘村钩鐨凱ARP鍒嗚銆侟/p>
(Only for Reference)
鍔ㄧ墿瀹為獙
Animal Models: 鐨笅绉绘 HT-29, A431, Colo205, H-460, SF763T, C6, A375,鎴 MDA-MB-435鐨勯泴鎬u/nu灏忛紶,鎼哄甫琛ㄨ揪鑽у厜绱犻叾 PC-3M鑲跨槫鐨勯泟鎬u/nu灏忛紶
Formulation: 閰嶅埗浣滀负缇х敳鍩虹氦缁寸礌鎮诞娑诧紝鎴栦綔涓烘煚妾吀缂撳啿娑?pH 3.5)
Dosages: 锝?0 mg/kg
Administration: 鍙ｆ湇澶勭悊锛屾瘡澶╀竴娆狘/p>
(Only for Reference)
鍙傝€冩枃鐚?/b>
[1] Sun L, et al. J Med Chem, 2003, 46(7), 1116-1119.
[2] Mendel DB, et al. Clin Cancer Res, 2003, 9(1), 327-337.
[3] O'Farrell AM, et al. Blood, 2003, 101(9), 3597-3605.
[4] Abrams TJ, et al. Mol Cancer Ther, 2003, 2(10), 1011-1021.
[5] Yee KW, et al. Blood, 2004, 104(13), 4202-4209.
[6] Ikezoe T, et al. Mol Cancer Ther, 2006, 5(10), 2522-2530.
瀹夊叏淇℃伅
| 鍥惧舰鎴栧嵄瀹虫爣蹇桙/td> |  |
| 鎻愮ず璇?/td> | Danger |
| 鍗遍櫓璇存槑 | H360 H372 |
| 闃茶寖璇存槑 | P201 P308+P313 |
| WGK | 2 |
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