鍩烘湰淇℃伅
| 鍒嗗瓙寮廃/td> | C21H22Cl2FN5O |
| 鍒嗗瓙閲廃/td> | 450.34 |
| 瀛樺偍鏉′欢 | Freezer -20鈩傸/td> |
浜у搧鎻忚堪
Crizotinib (PF-02341066) 鍏嬪攽鏇垮凹鏄竴绉嶆湁鏁堢殑c-Met鍜孉LK鎶戝埗鍓傦紝鍦ㄧ粏鑳炶瘯楠屼腑IC50鍒嗗埆涓?1 nM 鍜 24 nM銆傚畠鍚屾椂涔熸槸鏈夋晥鐨凴OS1鎶戝埗鍓傦紝鍏禟i鍊煎皬浜?.025 nM銆侟/p>
闈剁偣锛圛C50 & Targe锛堻/b>
ALK,24 nM (cell free)
c-Met,11 nM (A498 cells)
浣撳鐮旂┒
PF-2341066浣滅敤浜巑IMCD3灏忛紶鍜孧DCK鐘笂鐨粏鑳烇紝浣滅敤浜巆-Met纾烽吀鍖栦綔鐢ㄦ椂鍏锋湁鐩镐技鏁堟灉锛孖C50鍒嗗埆涓? nM 鍜?0 nM銆侾F-2341066浣滅敤浜庤〃杈綾-Met ATP-缁撳悎浣嶇偣绐佸彉鍨媀1092I 鎴朒1094R鎴 P-鐜獊鍙 M1250T 鐨凬IH3T3 缁嗚優锛屽叿鏈夌浉浼肩殑娲绘€э紝涓旀椿鍔涘楂橈紝IC50鍒嗗埆涓?9 nM,2 nM 鍜?5 nM,鑰屼綔鐢ㄤ簬琛ㄨ揪閲庣敓鍨嬪彈浣撶殑NIH3T3 缁嗚優鏃讹紝IC50涓?3 nM銆俒1] 鐩稿弽, 瑙傚療鍒癙F-2341066浣滅敤浜庤〃杈綾-Met娲诲寲鐜獊鍙樺瀷Y1230C 鍜孻1235D鐨勭粏鑳炴椂锛屼笌浣滅敤浜庨噹鐢熷瀷鍙椾綋鐩告瘮锛屾晥鏋滃彂鐢熸樉钁楁敼鍙橈紝IC50鍒嗗埆涓?27 nM 鍜?2 nM銆侾F-2341066 浣滅敤浜庡垎鍒〃杈惧唴婧愭€-Met 绐佸彉浣揜988C鍜 T1010I 鐨凬CI-H69 鍜孒OP92 缁嗚優锛屼篃鏈夋晥鎶戝埗c-Met 纾烽吀鍖? IC50鍒嗗埆涓?3 nM 鍜?6 nM銆備笌浣滅敤浜巆-Met鐩告瘮锛孭F-2341066浣滅敤浜嶸EGFR2 鍜孭DGFRβ RTKs, 閫夋嫨鎬ч珮1000澶氬€嶏紝浣滅敤浜嶪RK鍜孡ck閫夋嫨鎬ч珮250澶氬€嶏紝浣滅敤浜嶵ie2, TrkA,鍜孴rkB閫夋嫨鎬ч珮40鍒?0鍊嶃€侾F-2341066 浣滅敤浜嶳ON鍜 Axl RTKs鏃堕€夋嫨鎬т负20鍒?0鍊嶃€傜浉鍙嶏紝PF-2341066 浣滅敤浜庤〃杈続LK RTK 鐨勬牳纾疯泲鐧 (NPM)- 闂村彉鎬ф穻宸寸槫婵€閰?ALK) 鑷寸檶铻嶅悎绐佸彉浣撳拰 KARPAS299浜洪棿鍙樻€уぇ缁嗚優娣嬪反鐦?ALCL)缁嗚優绯绘椂鍏锋湁鐩歌繎鐨処C50鍊硷紝涓?4 nM銆侾F-2341066鎶戝埗c-Met渚濊禆鐨勭檶缁嗚優鐨勮偪鐦よ〃鐜板瀷锛屽拰鍐呯毊缁嗚優鐨勮绠＄敓鎴愯〃鐜板瀷銆侾F-2341066鎶戝埗浜篏TL-16鑳冪檶缁嗚優鐢熼暱锛孖C50涓?.7 nM銆侾F-2341066璇卞 GTL-16缁嗚優鍑嬩骸锛孖C50 涓?.4 nM銆侾F-2341066 鎶戝埗HGF鍒烘縺鐨勪汉NCI-H441鑲虹檶缁嗚優杩佺Щ鍜屽叆渚碉紝IC50鍒嗗埆涓?1 nM 鍜?.1 nM銆侾F-2341066鎶戝埗 MDCK缁嗚優鏁ｅ皠锛孖C50涓?6 nM銆侾F-2341066 鎶戝埗HGF-鍒烘縺鐨刢-Met纾烽吀鍖?缁嗚優瀛樻椿锛屽拰Matrigel鍏ヤ镜锛孖C50鍒嗗埆涓?1 nM, 14 nM鍜?5 nM銆傛澶? PF-2341066鎶戝埗绾ょ淮铔嬬櫧鑳朵腑鐨勮娓呭埡婵€鐨 HMVEC鍒嗘敮灏忕褰㈡垚 (褰㈡垚琛€绠?銆俒1] PF-2341066 浣滅敤浜嶬arpas299 鎴朣U-DHL-1 ALCL缁嗚優锛屼篃鏈夋晥鎶戝埗 NPM-ALK纾烽吀鍖栵紝IC50 涓?4 nM銆侾F-2341066 鏈夋晥鎶戝埗缁嗚優澧炴畺锛屼即闅忕潃浣跨粏鑳炲懆鏈熷仠鍦℅(1)-S鏈燂紝涓旇瀵 ALK闃虫€х殑 ALCL 缁嗚優鍑嬩骸锛孖C50涓?0 nM, 浣嗘槸浣滅敤浜嶢LK闃存€х殑娣嬪反鐦ょ粏鑳炲垯鏃犳晥鏋溿€ [2] 姝ゅ, PF-2341066 鎶戝埗楠ㄨ倝鐦ょ殑涓€浜涙椿鍔ㄨ涓猴紝鍙婂叾鑲跨槫鐢熼暱 (渚嬪,澧炴畺鍜屽瓨娲?鍜岃浆绉 (渚嬪锛屽叆渚靛拰褰㈡垚鍏嬮殕)銆俒3]
浣撳唴鐮旂┒
PF-2341066姣忓ぉ鎸?0 mg/kg鍜?5 mg/kg鍓傞噺澶勭悊GTL-16 妯″瀷, 寮曡捣澶ц偪鐦 (浣撶Н澶т簬600 mm3) 鏄庢樉琛伴€€锛屼笖鎸?3澶╁鐞嗘棩绋嬪鐞嗗悗锛屽钩鍧囪偪鐦や綋绉檷浣?0%銆傚湪鍙︿竴椤圭爺绌朵腑, PF-2341066澶勭悊3涓湀浠ヤ笂锛屽畬鍏ㄦ姂鍒禛TL-16鑲跨槫鐢熼暱锛孭F-2341066姣忓ぉ鎸?0 mg/kg鍓傞噺澶勭悊灏忛紶锛?涓湀鍚庯紝鍙湁1/12灏忛紶鐨勮偪鐦ょ敓闀垮緱鍒版彁楂樸€侾F-2341066姣忓ぉ鎸?0 mg/kg鍓傞噺澶勭悊NCI-H441 NSCLC 妯″瀷澶勭悊鍛ㄦ湡涓?8澶╋紝瑙傚療鍒板钩鍧囪偪鐦や綋绉檷浣?3%銆侾F-2341066 姣忓ぉ鎸?0 mg/kg鍓傞噺浣滅敤浜 Caki-1 RCC妯″瀷锛屽鐞嗗懆鏈熶负33澶╋紝瑙傚療鍒板钩鍧囪偪鐦や綋绉檷浣?3%锛屼笖姣忕鑲跨槫浣撶Н闄嶄綆鑷冲皯30%銆侾F-2341066姣忓ぉ鎸 50 mg/kg鍓傞噺浣滅敤浜 U87MG 鎭舵€ц兌璐ㄧ槫鎴朠C-3鍓嶅垪鑵虹檶绉绘鐦ゆā鍨?鍑犱箮瀹屽叏鎶戝埗鑲跨槫鐢熼暱锛屽湪瀹為獙鏈€鍚庝竴澶╋紝鎶戝埗鍒嗗埆杈?7% 鎴?4%銆傜浉鍙? PF-2341066姣忓ぉ鎸?0 mg/kg鍓傞噺鍙ｆ湇缁欒嵂澶勭悊 MDA-MB-231 涔宠吅鐧屾ā鍨?鎴 DLD-1 缁撹偁鐧屾ā鍨嬶紝涓嶄細鏄捐憲鎶戝埗鑲跨槫鐢熼暱銆侾F-2341066姣忓ぉ鎸?2.5 mg/kg, 25 mg/kg, 鍜?0 mg/kg鍓傞噺浣滅敤浜 GTL-16 鑲跨槫锛岃瀵熷埌CD31闃虫€у唴鐨粏鑳炴樉钁楅檷浣庯紝杩欑浣滅敤瀛樺湪鍓傞噺渚濊禆鎬э紝璇存槑 MVD 鍙楁姂鍒讹紝涓斿叿鏈夌浉鍏崇殑鎶楃檶楂樻晥鎬э紝杩欑浣滅敤涔熷瓨鍦ㄥ墏閲忎緷璧栨€с€侾F-2341066 浣滅敤浜嶨TL-16 鍜 U87MG 妯″瀷锛屾樉钁楅檷浣庝汉VEGFA 鍜孖L-8琛€娴嗘按骞筹紝杩欑浣滅敤瀛樺湪鍓傞噺渚濊禆鎬с€侾F-2341066鍙ｆ湇澶勭悊GTL-16 鑲跨槫锛岃瀵熷埌纾烽吀鍖栫殑c-Met, Akt, Erk, PLCλ1,鍜 STAT5姘村钩鏄捐憲鍙楁姂鍒躲€俒1]PF-2341066 姣忓ぉ鎸?00 mg/kg鍓傞噺鍙ｆ湇澶勭悊鎼哄甫Karpas299 ALCL 绉绘鐦ょ殑SCID Beige 灏忛紶锛屽叿鏈夋姉鐧岄珮鏁堟€э紝杩欑浣滅敤瀛樺湪鍓傞噺渚濊禆鎬э紝澶勭悊15澶╋紝鎵€鏈夎偪鐦ゅ畬鍏ㄨ“閫€銆傛澶? PF-2341066鎶戝埗鍏抽敭NPM-ALK淇″彿璋冭妭鍣? 鍖呮嫭纾疯剛閰禖-γ, 淇″彿杞鍣紝鍙婅浆褰曞洜瀛?, 缁嗚優澶栦俊鍙疯皟鑺傛縺閰? 鍜孉kt鐨勬縺娲诲墏锛岃繖浜涗笌 NPM-ALK 纾烽吀鍖栧拰鍔熻兘鍙楁姂鍒剁浉鍏炽€俒2] PF-2341066 鎶戝埗楠ㄨ倝鐦ょ殑涓€浜涙椿鍔ㄨ涓猴紝鍙婂叾鑲跨槫鐢熼暱(渚嬪, 澧炴畺鍜屽瓨娲?鍜岃浆绉 (渚嬪锛屽叆渚靛拰褰㈡垚鍏嬮殕)銆侾F-2341066鍙ｆ湇楗插杺瑁搁紶锛屾姂鍒剁敓闀垮拰鐩稿叧鐨勯鑲夌槫瑁搁紶绉绘鐦ょ殑楠ㄥ熀璐ㄧ殑褰㈡垚銆俒3] PF-2341066 鎸?0 mg/kg 鍓傞噺澶勭悊 c-MET-鎵╁鐨凣TL-16绉绘鐦わ紝寮曡捣鑲跨槫琛伴€€锛岃繖涓?8F-FDG 鎽勫彇鐨勭紦鎱㈤檷浣庣浉鍏筹紝涓旈檷浣庤憽绯栫硸杞繍铔嬬櫧 1, GLUT-1鐨勮〃杈俱€俒4]
婵€閰跺疄楠孅/b>
鐢熷寲婵€閰跺疄楠孃浣跨敤杩炵画鑰﹀悎鐨勫垎鍏夊厜搴︽祴瀹歝-Met鍌寲娲绘€э紝閫氳繃鍒嗘瀽NADH娑堣€楃巼鑰屾祴瀹歝-Met璇卞鐨凙DP浜ч噺锛岃繖绉嶄綔鐢ㄥ叿鏈夋椂闂翠緷璧栨€с€傚湪 340 nm澶勪娇鐢ㄥ垎鍏夊厜搴︽硶鍦ㄦ寚瀹氭椂闂寸偣娴嬪畾鍚稿厜鍊肩殑闄嶄綆鑰岃绠桸ADH鐨勬秷鑰楅噺銆備负浜嗘祴瀹欿i鍊? 鍦ㄥ惈瀹為獙璇曞墏鐨勫疄楠屽瓟涓姞鍏ヤ笉鍚屾祿搴F-2341066锛岀劧鍚庡湪37oC涓嬫俯鑲?0鍒嗛挓銆傚姞鍏-Met閰跺紑濮嬭繘琛屽疄楠屽弽搴斻€侟/p>
缁嗚優瀹為獙
Cell lines: GTL-16鑳冪檶缁嗚優鍜孴47D涔宠吅鐧岀粏鑳濣/p>
Concentrations: 0 nM-256 nM
Incubation Time: 1灏忔椂
Method:GTL-16鑳冪檶缁嗚優鍜孴47D涔宠吅鐧岀粏鑳炴帴绉嶅湪96瀛旀澘涓婏紝瀛斾腑鍚煿鍏诲熀锛屽煿鍏诲熀涓惈10% 鑳庣墰琛€娓?FBS)锛岀劧鍚庤浆绉诲埌鏃犺娓呭煿鍏诲熀涓?b class="text-danger">鍚?.04%鐗涜娓呰泲鐧?BSA)锛屽鐞 24灏忔椂銆 鍦ㄨ皟鏌ラ厤浣撲緷璧栫殑RTK 纾烽吀鍖栧疄楠屼腑锛屽姞鍏ョ浉搴旂殑鐢熼暱鍥犲瓙锛屽鐞?0鍒嗛挓銆傜粏鑳炲拰 PF-2341066鍜?鎴栭€傚綋閰嶄綋鍦ㄦ寚瀹氭椂闂存俯鑲?灏忔椂锛岀劧鍚庝娇鐢ㄥ惈 1 mmol/L Na3VO4鐨凥BSS鍐叉礂缁嗚優涓€娆?鐒跺悗浠庣粏鑳炰腑鑾峰緱铔嬬櫧瑁傝В鐗┿€傞殢鍚?閫氳繃澶瑰績閰惰仈鍏嶇柅鍚搁檮璇曢獙娉曚娇鐢ㄧ壒瀹氱殑鎹曡幏鎶椾綋鍦?6瀛旀澘涓婃祴瀹氶€夊畾铔嬬櫧婵€閰剁殑纾烽吀鍖栵紝浣跨敤鐗圭偣妫€娴嬫姉浣撴祴瀹氱７閰稿寲鐨勯叒姘ㄩ吀娈嬪熀銆傛姉浣撳寘琚殑瀹為獙鏉?a) 鍦ㄨ泲鐧借瑙ｇ墿瀛樺湪鏃讹紝鍦?oC涓嬭繃澶淃(b)鍦ㄦ憾浜嶱BS鐨?% Tween-20 涓啿娲?娆狖(c)鍦ㄨ荆鏍硅繃姘у寲鐗╅叾鏍囪鐨勬姉鎬荤７閰革紙PY-20锛夋姉浣擄紙1:500锛変腑娓╄偛20鍒嗛挓;(d) 鍐嶆鍐叉礂7娆狖(e)鍦?,3鈥?5,5鈥?鍥涚敳鍩鸿仈鑻兒杩囨哀鍖栫墿閰跺簳鐗╀腑娓╄偛锛屽紑濮嬫樉绀哄弽搴旓紝鍔犲叆0.09 N H2SO4缁堟鍙嶅簲; (f)鍦?50 nm 澶勪娇鐢ㄥ垎鍏夊厜搴﹁娴嬪畾鍚稿厜搴︺€侟/p>
(Only for Reference)
鍔ㄧ墿瀹為獙
Animal Models: 鎼哄甫NCI-H441,鎴朌LD-1,鎴朚DA-MB-231鐨勯泴鎬у拰闆勬€u/nu灏忛紶
Formulation: --
Dosages: 12.5 mg/kg/day, 25 mg/kg/day, 鍜?0 mg/kg/day
Administration: 鍙ｆ湇澶勭悊
(Only for Reference)
鍙傝€冩枃鐚?/p>
鍙傝€冩枃鐚?/b>
[1] Zou HY, et al. Cancer Res. 2007, 67(9), 4408-4417.
[2] Christensen JG, et al. Mol Cancer Ther. 2007, 6(12 Pt 1), 3314-3322.
[3] Sampson ER, et al. J Bone Miner Res. 2011, 26(6), 1283-1294.
[4] Cullinane C, et al. J Nucl Med. 2011, 52(8), 1261-1267.
[5] Gong HC, et al. Int J Proteomics. 2011, 2011, 215496.
[6] Zou HY, et al. Proc Natl Acad Sci U S A. 2015, 112(11):3493-8
瀹夊叏淇℃伅
| 闃茶寖璇存槑 | P262 |
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